CN1688582A - Fused azole-pyrimidine derivatives - Google Patents

Abstract

The present invention relates to hovel fused azolepyrimidine derivatives, processes for preparing them and pharmaceutical preparations containing them. The fused azolepyrimidine derivatives of the present invention exhibit enhanced potency for phosphotidylinositol-3-kinase (P13K) inhibition, especially for PI3K-gamma inhibition and can be used for the prophylaxis and treatment of diseases associated with P13K and particularly with P13K-gamma activity. More specifically, the azole derivatives of the present invention are useful for treatment and prophylaxis of diseases as follows: inflammatory and immunoregulatory disorders, such as asthma, atopic dermatitis, rhinitis, allergic diseases, chronic obstructive pulmonary disease (COPD), septic shock, joint diseases, autoixnmune pathologies such as rheumatoid arthritis, and Graves' disease, cancer, myocardial contractility disorders, heart failure, thromboembolism, ischemia, and atherosclerosis. The compounds of the present invention are also useful for pulmonary hypertension, renal failure, cardiac hypertrophy, as well as neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, diabetes and focal ischemia, since the diseases also relate to P13K activity in a human or animal subject.

Description

Fused pyrrole-pyrimidine derivatives

Detailed description of the invention

technical field

The present invention relates to novel fused pyrropyrimidine derivatives, processes for their preparation and pharmaceutical compositions containing them. The fused pyrrole pyrimidine derivatives of the present invention show enhanced phosphatidylinositol-3-kinase (PI3K) inhibitory effect, especially PI3K-γ inhibition, and can be used for the prevention and treatment of diseases related to PI3K, especially PI3K-γ activity .

More specifically, the fused pyrropyrimidine derivatives of the present invention are useful for the treatment and prevention of the following diseases: inflammatory and immunomodulatory diseases such as asthma, atopic dermatitis, rhinitis, allergic diseases, chronic obstructive pulmonary disease (COPD), Septic shock, joint disease, autoimmune pathology such as rheumatoid arthritis, and Graves' disease, cancer, myocardial systolic disease, heart failure, thromboembolism, ischemia and atherosclerosis.

The compounds of the present invention are also useful in pulmonary hypertension, renal failure, cardiac hypertrophy, and neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, diabetes and focal ischemia, because these diseases are also associated with PI3K in human or animal patients. activity related.

Background technique

Signal transduction pathways derived from chemoattractant factors, which activate heterotrimeric G-protein coupled receptors (GPCR ), thereby triggering complex downstream intracellular events. Signal transduction in one of the pathways leading to intracellular free Ca2 ⁺ mobilization, cytoskeleton reorganization, and directional movement is dependent on lipid-derived second messengers generated by phosphoinositide 3-kinase (PI3K) activity [1, 2].

PI3K phosphorylates the D3-hydroxyl position of the membrane phosphoinositide-4,5-bisphosphate (PtdIns(4,5)P ₂ ) to give phosphoinositide-3,4,5-triphosphate (PtdIns(3, 4, 5) P ₃ ). The PI3K family consists of three classes based on membrane specificity and protein structure [4-6]. Of particular interest in leukocyte motility are the class of IPI3Ks, which are all involved in receptor-induced inflammatory cell responses and are further divided into subclasses IA (p110α, β, δ) and IB (p110γ).

Class IA enzymes (p110α, β, δ) associate with the p85 linker subunit, which contains two SH2 domains, to form a heterodimeric complex that recognizes phosphotyrosine YxxM motifs, produces and accepts Association of body tyrosine kinases with subsequent activation of enzymes by receptor tyrosine kinases [1,2]. The class IA subtype is thought to be involved in cell proliferation and carcinogenesis, and the IA subtype binds activated rat oncogenes found in many cancers to express their enzymatic activation. It was also found that p10α and β play an important role in human cancer growth [3].

The class IB(p110γ) enzyme, whose expression is largely restricted to leukocytes, is activated by G protein βγ complexes, executing the downflow of seven transmembrane chemoattractant receptors [7-9]. The p101 linker protein, which bears no analogy to any other known protein, is essential for the G protein βγ response of p10γ (PI3Kγ) [10-12].

Recent studies of functional PI3Kγ deficient (PI3Kγ-/- mice) that survive, reproduce, and exhibit normal lifespan in routine mouse laboratories have shown that neutrophils respond to GPCR agonists such as fMLP, C5a, or IL- 8 can not produce PtdIns(3,4,5)P ₃ when stimulated. This suggests that PI3Kγ is the only PI3K coupled to these GPCRs in these cells [13-16]. Furthermore, PtdIns(3,4,5)P3 _- dependent activation of protein kinase B (PKB) was also absent in those neutrophils, while PKB could still be activated by GM-CSF or IgG/C3b-coated Zymosan is activated by p110α, β or δ. While, in response to G-protein delivery, PLCβ activation was intact, PI3Kγ-/- mice displayed impaired thymocyte development and increased neutrophil, monocyte, and eosinophil populations [14]. Furthermore, neutrophils and macrophages isolated from PI3Kγ-/- mice display severe defects in motility and respiratory bursts in response to GPCR agonists and chemotropics [14, 16]. Expression of PI3Kγ was also examined in transgenic mice expressing green fluorescent protein (GFP) under the control of an endogenous PI3Kγ promoter. GFP is detected in spleen and bone marrow cells and neutrophils, suggesting that expression of PI3Kγ is restricted to hematopoietic cells [15]. Taken together, the class IB phosphoinositide 3-kinase PI3Kγ appears to be critical in the control of leukocyte motility and, therefore, the development of isoform-selective inhibitors of PI3Kγ should be an attractive anti-inflammatory strategy.

Hypertrophic responses can be elicited by PI3K signaling pathways, and a recent study published today identifies a role for the PTEN-PI3Kγ pathway in modulating cardiac contractility, however, PI3Kα mediates the cell size changes observed during cardiac hypertrophy to heart failure, and PI3Kγ plays a role in cardiac contractility Sexual negative regulators.

PTEN is a dual-specificity protein phosphatase involved in cell growth signaling as a phosphoinositide phosphatase, and the tumor suppressor TPEN was shown to dephosphorylate phosphoinositide 3,4,5-triphosphate (PIP3), which is due to PI3K An important second messenger that acts specifically. PTEN reduces the level of PIP3 in cells and antagonizes the cellular signal transmitted by PI3K. It has also been reported that expression of dominant negative PTEN in rat cardiomyocytes in tissue culture causes hypertrophy.

PI3Kγ modulates baseline cAMP levels, controlling cellular contractility, and this study also showed that changes in baseline cAMP levels contribute to increased contractility in mutant xenogeneic mice [17].

Thus, the findings of this study show that PI3Kγ is involved in cardiac contractility and thus inhibitors would be effective in the treatment of congestive heart failure, ischemia, pulmonary hypertension, renal failure, cardiac hypertrophy, arteriosclerosis, thromboembolism and diabetes.

PI3K inhibitors that are expected to block signal transduction by GPCRs and activation of various immune cells should have a broad anti-inflammatory spectrum and be effective in the treatment of inflammatory and immunomodulatory diseases,[2] including asthma, atopic dermatitis, rhinitis , allergic disease, chronic obstructive pulmonary disease (COPD), septic shock, joint disease, autoimmune pathology such as rheumatoid arthritis, and Graves disease, diabetes mellitus, cancer, myocardial contractility disease, thromboembolism [18] and arterial Sclerosis.

Certain PI3-kinase inhibitors have been identified: wortmannin, isolated by Penicilliumwortmannii as a mycotoxin [19], the most related, but undercharacterized demethoxygreen glomycin and LY294002, a broad-spectrum kinase inhibitor Morpholino derivatives of quercetin [20].

US3644354 discloses 5-substituted 2,3 dihydroimidazo[1,2-c]quinazolines represented by the general formula as hypotensive drugs and coronary artery dilators:

Wherein R and R ⁰ are H, lower alkyl, lower alkenyl respectively; R' and R" are H, halogen, lower alkyl, lower alkoxy respectively

or

However, there are no references disclosing fused pyrropyrimidines that also have PI3K inhibitory activity, such as, but not limited to, pyrrole-quinazoline, pyrrole-pyridopyrimidine, pyrrole-pyrimidopyrimidine, pyrrole-pyrimidopyrazine, pyrrole -pyrimidotriazine, pyrrole-pteridine, pyrrole-pyrimidotetrazine and an acylated amine attached to the 5 or 6 position of a fused pyrrole pyrimidine or -CR ⁵ R ⁶ -C(O)-(R ⁵ is H Or C _1-6 alkyl and R ⁶ is halogen, H or other derivatives of C _1-6 alkyl).

There remains a need to develop compounds for the treatment and prevention of inflammatory, cancer and/or cardiac contractility disorders associated with PI3K activity.

Summary of the invention

As a result of extensive studies on the chemical modification of fused pyrrole pyrimidine derivatives, the present inventors found that compounds of a new chemical structure related to the present invention have PI3K inhibitory activity, especially PI3Kγ inhibitory activity, and based on this discovery, completed the present invention invention.

The present invention provides novel fused pyrrole pyrimidine derivatives of formula (I), their tautomeric and stereoisomeric forms and their salts:

in

X represents CR ⁵ R ⁶ or NH;

Y ¹ means CR ³ or N;

exist The chemical bond between represents a single bond or a double bond,

The premise is that

when When denoting a double bond, ^Y2 and ^Y3 denote ^CR4 or N, respectively, and

表示单键时，Y²和Y³分别表示CR³R⁴或NR⁴；when

When representing a single bond, Y ² and Y ³ represent CR ³ R ⁴ or NR ⁴ respectively;

Z ¹ , Z ² , Z ³ and Z ⁴ respectively represent CH, CR ² or N;

R ¹ represents an aryl group optionally having 1-3 substituents selected from R ¹¹ , a C _3-8 alkyl optionally having 1-3 substituents selected from R ¹¹ ,

C _1-6 alkyl optionally substituted by aryl, heteroaryl, C _1-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogens,

C _1-6 alkoxy optionally substituted by carboxy, aryl, heteroaryl, C _1-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogens, or

3-15 membered mono- or bicyclic heterocycles, which are saturated or unsaturated, contain 1-3 heteroatoms selected from N, O and S and optionally carry ^1-3 substituents selected from R ,

in

R ¹¹ means

Halogen, nitro, hydroxyl, cyano, carboxyl, amino, N-(C _1-6 alkyl) amino, N-(hydroxy C _1-6 alkyl) amino, N, N-di(C _1-6 alkane base) amino, N-(C _1-6 acyl) amino, N-(formyl)-N-(C _1-6 alkyl) amino, N-(C _1-6 alkylsulfonyl) amino, N- (Carboxyl C _1-6 alkyl)-N-(C _1-6 alkyl) amino, N-(C _1-6 alkoxycarbonyl) amino, N-[N, N-two (C _1-6 alkane Base) aminomethylene] amino, N-[N, N-two (C _1-6 alkyl) amino (C _1-6 alkyl) methylene] amino, N-[N, N-two (C _1-6 alkyl) amino C _2-6 alkenyl] amino, aminocarbonyl, N-(C _1-6 alkyl) aminocarbonyl, N, N-two (C _1-6 alkyl) aminocarbonyl, C _{3 -8} cycloalkyl, C _1-6 alkylthio, C _1-6 alkylsulfonyl, aminosulfonyl, C _1-6 alkoxycarbonyl,

N-arylamino, wherein the aryl part optionally has 1-3 substituents selected from R ¹⁰¹ , N-(aryl C _1-6 alkyl) amino, wherein the aryl part optionally With 1-3 substituents selected from R ¹⁰¹ , aryl C _1-6 alkoxycarbonyl, wherein the aryl moiety optionally has 1-3 substituents selected from R ¹⁰¹ ,

C _1-6 alkyl optionally substituted by mono-, di- or tri-halogen, amino, N-(C _1-6 alkyl)amino or N,N-di(C _1-6 alkyl)amino,

C _1-6 alkoxy optionally substituted by mono-, di- or tri-halogen, amino, N-(C _1-6 alkyl)sulfonamide or N-(aryl)sulfonamide, or

A 5-7 membered saturated or unsaturated ring containing 1-3 heteroatoms selected from O, S and N and optionally carrying 1-3 substituents selected from R ¹⁰¹ ,

in

R ¹⁰¹ means

Halogen, carboxyl, amino, N-(C _1-6 alkyl) amino, N, N-di(C _1-6 alkyl) amino, aminocarbonyl, N-(C _1-6 alkyl) aminocarbonyl, N , N-two (C _1-6 alkyl) aminocarbonyl, pyridyl,

C _1-6 alkyl optionally substituted by cyano or mono-, di- or tri-halogen, or

Optionally cyano, carboxyl, amino, N-(C _1-6 alkyl)amino, N,N-di(C _1-6 alkyl)amino, aminocarbonyl, N-(C _1-6 alkyl) Aminocarbonyl, N, N-di(C _1-6 alkyl) aminocarbonyl or mono-, di- or tri-halogen substituted C _1-6 alkoxy;

R ² represents hydroxyl, halogen, nitro, cyano, amino, N-(C _1-6 alkyl) amino, N, N-two (C _1-6 alkyl) amino, N-(hydroxyl C _1-6 Alkyl) amino, N-(hydroxy C _1-6 alkyl)-N-(C _1-6 alkyl) amino, C _1-6 acyloxy, amino C _1-6 acyloxy, C _2-6 alkenyl, aryl,

5-7 membered saturated or unsaturated heterocycle containing 1-3 heteroatoms selected from O, S and N, optionally substituted by hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, oxo , amino, amino C _1-6 alkyl, N-(C _1-6 alkyl) amino, N, N-di(C _1-6 alkyl) amino, N-(C _1-6 acyl) amino, N -(C _1-6 alkyl) carbonylamino, phenyl, phenyl C _1-6 alkyl, carboxyl, C _1-6 alkoxycarbonyl, aminocarbonyl, N-(C _1-6 alkyl) aminocarbonyl Or N, N-two (C _1-6 alkyl) amino substitution,

-C(O)-R ²⁰

in

R ²⁰ represents C _1-6 alkyl, C _1-6 alkoxy, amino, N-(C _1-6 alkyl) amino, N, N-two (C _{1- 6} alkyl) amino, N-( C _1-6 acyl) cyano, or a 5-7 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms selected from O, S and N, and optionally replaced by C _1-6 alkyl, C _1-6 alkoxy, oxo, amino, N-(C _1-6 alkyl) amino, N, N-di(C _1-6 alkyl) amino, N-(C _1-6 acyl) amino, Phenyl or benzyl substitution,

C _1-6 alkyl optionally substituted by R ²¹ ,

or

C _1-6 alkoxy optionally substituted by R ²¹ ,

in

R ²¹ represents cyano, mono-, di- or tri-halogen, hydroxyl, amino, N-(C _1-6 alkyl) amino, N, N-two (C _1-6 alkyl) amino, N-( Hydroxy C _1-6 alkyl) amino, N-(halophenyl C _1-6 alkyl) amino, amino C _2-6 alkenyl, C _1-6 alkoxy, hydroxy C _1-6 alkoxy , -C(O)-R ²⁰¹ , -NHC(O)-R ²⁰¹ , C _3-8 cycloalkyl, isoindolyl, phthalimide, 2-oxo-1,3-oxo Oxazolidinyl, aryl, or 5 or 6 membered saturated or unsaturated heterocyclic rings, which contain 1-4 heteroatoms selected from O, S and N, optionally replaced by hydroxyl, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 alkoxycarbonyl, hydroxy C _1-6 alkoxy, oxo, amino, amino C _1-6 alkyl, N-(C _1-6 alkyl) amino, N , N-di(C _1-6 alkyl) amino, N-(C _1-6 acyl) cyano or benzyl substitution,

in

R ²⁰¹ represents hydroxyl, amino, N-(C _1-6 alkyl) amino, N,N-di(C _1-6 alkyl) amino, N-(halogenated phenyl C _1-6 alkyl) amino, C _1-6 alkyl, amino C _1-6 alkyl, amino C _2-6 alkenyl, C _1-6 alkoxy, or 5 or 6 membered saturated or unsaturated heterocyclic rings containing 1-4 optional A heteroatom from O, S and N, optionally substituted by hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, hydroxy C _1-6 alkoxy, oxo , amino, N-(C _1-6 alkyl) amino, N, N-di(C _1-6 alkyl) amino, N-(C _1-6 acyl) cyano or benzyl substitution,

R ³ represents H, halogen, aminocarbonyl or C _1-6 alkyl optionally substituted by aryl C _1-6 alkoxy or mono-, di- or tri-halogen;

R ⁴ represents H or C _1-6 alkyl;

^R represents H or C _1-6 alkyl; and

R ⁶ represents halogen, H or C _1-6 alkyl.

The compounds of the present invention exhibit PI3K inhibitory activity and PI3Kγ inhibitory activity, therefore, they are suitable for the production of medicaments and pharmaceutical compositions, which can be used for the treatment and prevention of PI3K and/or PI3Kγ-related diseases, such as inflammatory and immunomodulatory diseases, such as asthma, Atopic dermatitis, rhinitis, allergic disease, chronic obstructive pulmonary disease (COPD), septic shock, joint disease, autoimmune pathology such as rheumatoid arthritis, and Graves disease, myocardial contractility disease, heart failure, thromboembolism , ischemia, cardiac hypertrophy, arteriosclerosis and cancers such as skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, stomach cancer, brain tumor, leukemia, etc. .

The compounds of the present invention are also useful in the treatment of pulmonary hypertension, renal failure, Huntington's disease and cardiac hypertrophy, as well as neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, diabetes and focal ischemia, because these diseases are also associated with PI3K activity in human or animal patients.

The present invention also relates to a method for treating or preventing symptoms or diseases related to PI3K activity, especially PI3Kγ activity, in human or animal patients, which comprises administering to the patient a therapeutically effective amount of the fused compound represented by formula (I) Pyrropyrimidine derivatives, their tautomeric or stereoisomeric forms or their physiologically acceptable salts.

In addition, the present invention provides the use of the fused pyrrole pyrimidine derivative represented by formula (I), its tautomeric or stereoisomeric form or a physiologically acceptable salt thereof in the preparation of medicaments.

In one embodiment, the present invention provides a fused pyrrole pyrimidine derivative of formula (I), its tautomeric or stereoisomeric form or a salt thereof;

in

X represents CR ⁵ R ⁶ or NH;

Y ¹ means CR ³ or N;

exist The chemical bond between represents a single bond or a double bond,

The premise is that

表示双键时，Y²和Y³分别表示CR⁴或N，和when

When denoting a double bond, ^Y2 and ^Y3 denote ^CR4 or N, respectively, and

表示单键时，Y²和Y³分别表示CR³R⁴或NR⁴；when

When representing a single bond, Y ² and Y ³ represent CR ³ R ⁴ or NR ⁴ respectively;

Z ¹ , Z ² , Z ³ and Z ⁴ respectively represent CH, CR ² or N;

R ¹ means

C _1-6 alkyl optionally substituted by mono-, di- or tri-halogen, phenyl, methoxyphenyl, phenoxy or thienyl,

C _1-6 alkoxy optionally substituted by mono-, di- or tri-halogen, phenyl, methoxyphenyl, phenoxy or thienyl,

or

One of the following carbocyclic and heterocyclic rings selected from cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl , Isoxazolyl, imidazolyl, isoimidazolyl, pyrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4- Oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, phenyl, pyridyl , pyrazinyl, pyrimidinyl, pyridazinyl, 1-benzothienyl, benzothiazolyl, benzimidazolyl, 3H-imidazo[4,5-b]pyridyl, benzotriazolyl, ind Indolyl, indazolyl, imidazo[1,2-b]pyridyl, quinolinyl and 1,8-naphthyridyl,

in

The carbocycle and heterocycle are optionally substituted by 1-3 substituents selected from hydroxyl, halogen, nitro, cyano, carboxyl, amino, N-(C _1-6 alkyl)amino, N, N-two (C _1-6 alkyl) amino, N- (C _1-6 acyl) amino, N- (C _1-6 alkoxycarbonyl) amino, N- (formyl) -N- (C _{1 -6} alkyl) amino, N-[N, N-two (C _1-6 alkyl) aminomethylene] amino, N-[N, N- two (C _1-6 alkyl) amino (C _{1 -6} alkylene) methylene] amino, N-[N, N-di(C _1-6 alkyl) amino C _2-6 alkenyl] amino, C _1-6 alkylthio, C _1-6 Alkylsulfonyl, aminosulfonyl, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolidinyl, pyridyl, phenyl C _1-6 alkane Oxycarbonyl,

Thiazolyl optionally substituted by pyridyl,

By C _1-6 alkyl or C _1-6 alkoxy optionally substituted piperazinyl and

C _1-6 alkyl optionally substituted by mono-, di- or tri-halogen;

R ² represents hydroxyl, halogen, nitro, cyano, carboxyl, amino, N-(C _1-6 alkyl) amino, N-(hydroxyl C _1-6 alkyl) amino, N,N-two (C _{1 -6} alkyl) amino, N-(hydroxy C _1-6 alkyl)-N-(C _1-6 alkyl) amino, C _2-6 alkenyl, C _1-6 alkoxycarbonyl, aminocarbonyl, C _1-6 acyloxy, amino C _1-6 acyloxy, furyl, morpholino, phenyl, piperidino, aryl,

Pyrrolidinyl optionally substituted by C _1-6 amido,

Piperidino optionally substituted by hydroxy, C _1-6 alkyl, carboxyl, aminocarbonyl, N-(C _1-6 alkyl)aminocarbonyl or N,N-di(C _1-6 alkyl)aminocarbonyl base,

Piperazinyl optionally substituted by C _1-6 alkyl,

By cyano, mono-, di- or tri-halogen, hydroxyl, amino, N-(C _1-6 alkyl)amino, N-(hydroxyl C _1-6 alkyl)amino, N,N-di(C _1-6 alkyl) amino, C _3-6 cycloalkyl, tetrazolyl, tetrahydropyranyl, morpholino, phthalimido, 2-oxo-1,3-oxazolidine C _1-6 alkyl optionally substituted by phenyl,

-C(O)-R ²⁰¹ ,

Pyrrolidinyl optionally substituted by C _1-6 amido,

Piperidino optionally substituted by hydroxy, C _1-6 alkyl, carboxyl, aminocarbonyl, N-(C _1-6 alkyl)aminocarbonyl or N,N-di(C _1-6 alkyl)aminocarbonyl base or

Piperazinyl optionally substituted by C _1-6 alkyl,

in

R ²⁰¹ represents hydroxyl, amino, N-(C _1-6 alkyl) amino, N,N-di(C _1-6 alkyl) amino, N-(halogenated benzyl) amino, C _1-6 alkyl , C _1-6 alkoxy, tetrazolyl, tetrahydropyranyl, morpholino,

Pyrrolidinyl optionally substituted by C _1-6 amido,

Piperidino optionally substituted by hydroxy, C _1-6 alkyl, carboxyl, aminocarbonyl, N-(C _1-6 alkyl)aminocarbonyl or N,N-di(C _1-6 alkyl)aminocarbonyl base,

or

Piperazinyl optionally substituted by C _1-6 alkyl,

By cyano, mono-, di- or tri-halogen, hydroxyl, C _1-6 alkoxy, hydroxyl C _1-6 alkoxy, amino, N-(C _1-6 alkyl) amino, N, N -Di(C _1-6 alkyl)amino, pyrrolyl, tetrazolyl, tetrahydropyranyl, morpholino, phthalimido, 2-oxo-1,3-oxazolidinyl , phenyl, -C(O)-R ²⁰¹ optionally substituted C _1-6 alkoxy,

Pyrrolidinyl optionally substituted by C _1-6 amido,

Piperidino optionally substituted by hydroxy, C _1-6 alkyl, carboxyl, aminocarbonyl, N-(C _1-6 alkyl)aminocarbonyl or N,N-di(C _1-6 alkyl)aminocarbonyl base

or

Piperazinyl optionally substituted by C _1-6 alkyl,

in

R ²⁰¹ represents hydroxyl, amino, N-(C _1-6 alkyl) amino, N,N-di(C _1-6 alkyl) amino, N-(halogenated benzyl) amino, C _1-6 alkyl , C _1-6 alkoxy, amino C _2-6 alkenyl, tetrazolyl, tetrahydropyranyl, morpholino,

Pyrrolidinyl optionally substituted by C _1-6 amido,

Piperidino optionally substituted by hydroxy, C _1-6 alkyl, carboxyl, aminocarbonyl, N-(C _1-6 alkyl)aminocarbonyl or N,N-di(C _1-6 alkyl)aminocarbonyl base,

or

Piperazinyl optionally substituted by C _1-6 alkyl,

R ³ represents H, halogen, C _1-6 alkyl optionally substituted by aminocarbonyl, aryl C _1-6 alkoxy or mono-, di- or tri-halogen;

R ⁴ represents H or C _1-6 alkyl;

^R represents H or C _1-6 alkyl; and

R ⁶ represents halogen, H or C _1-6 alkyl.

In another embodiment, the present invention provides a fused pyrrole pyrimidine derivative of formula (I), its tautomeric or stereoisomeric form or a salt thereof:

in

X represents CR ⁵ R ⁶ or NH;

Y ¹ means N;

Y ² and Y ³ represent CR ³ R ⁴ ;

exist The chemical bond between represents a single bond,

Z ⁴ means CH;

Z ¹ , Z ² and Z ³ respectively represent N, CH or CR ² ;

R ¹ represents cyclopropyl, cyclopentyl, cyclohexyl, 2-furyl, 3-furyl, imidazolyl, pyrimidinyl, pyridazinyl, piperazinyl, 1,2,3-thiadiazolyl, 1 , 3-benzothiazolyl, quinolinyl, 3H-imidazo[4,5-b]pyridyl, 1H-pyrrol-2-yl optionally substituted by C _1-6 alkyl, by C _1-6 1H-pyrrol-3-yl optionally substituted by alkyl, pyrazolyl optionally substituted by 1 or 2 C _1-6 alkyl, isoxa optionally substituted by 1 or 2 C _1-6 alkyl Azolyl,

2-thienyl optionally substituted by chlorine, nitro, cyano or C _1-6 alkyl,

3-thienyl optionally substituted by chlorine, nitro, cyano or C _1-6 alkyl,

Piperidinyl optionally substituted by C _1-6 alkoxycarbonyl or benzyloxycarbonyl,

Phenyl optionally substituted by 1-3 substituents selected from the group consisting of: fluorine, chlorine, hydroxyl, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _{1 -6} alkoxycarbonyl, amino, N-(C _1-6 alkyl) amino, N-(C _1-6 acyl) amino, N-(C _1-6 alkoxycarbonyl) amino, N, N- Di(C _1-6 alkyl)amino, N-(formyl)-NC _1-6 alkylamino, C _1-6 alkylthio, C _1-6 alkylsulfonyl, sulfamoyl, pyrrolyl, Imidazolyl, pyrazolyl and piperazinyl optionally substituted by C _1-6 alkyl, pyridyl optionally substituted by 1 or 2 substituents selected from the group consisting of chlorine, hydroxyl, carboxyl, C _{1- 6} alkoxy, C _1-6 alkylthio, amino, N-(C _1-6 alkyl) amino, N-(hydroxyl C _1-6 alkyl) amino, N, N-two (C _1-6 Alkyl)amino, N-(C _1-6 acyl)amino, N-(C _1-6 alkyl)sulfonylamino, N-[N,N-di(C _1-6 alkyl)aminomethylene ] amino and C _1-6 alkyl optionally substituted by three halogens,

Piperazinyl optionally substituted by C _1-6 alkyl,

1,3-thiazolyl optionally substituted by 1 or 2 substituents selected from C _1-6 alkyl, pyridyl and N-(C _1-6 alkoxycarbonyl)amino,

Indolyl optionally substituted by C _1-6 alkyl,

Benzimidazolyl optionally substituted by C _1-6 alkyl or trihalogenated C _1-6 alkyl,

1,2,3-benzotriazolyl optionally substituted by C _1-6 alkyl,

1,8-naphthyridinyl optionally substituted by C _1-6 alkyl optionally substituted by trihalogen,

C _1-6 alkyl optionally substituted by trihalogen, phenyl, phenoxy or thienyl,

or

C _1-6 alkoxy optionally substituted by phenyl, phenoxy or thienyl;

R ² represents fluorine, chlorine, bromine, hydroxyl, nitro, vinyl, cyano, amino, aminoacetoxy, N-(C _1-6 alkyl) amino, N,N-two (C _1-6 alkane Base) amino, N-(hydroxy C _1-6 alkyl)-N-(C _1-6 alkyl) amino, 2-furyl, piperidino, morpholino, phenyl,

Pyrrolidinyl optionally substituted by acetylamino,

Piperidino optionally substituted by hydroxy,

Piperazinyl optionally substituted by methyl, benzyl, C _{alkoxycarbonyl} or aminocarbonyl,

C _1-6 alkyl optionally substituted by cyano, trifluoro, carboxyl, methoxycarbonyl, aminocarbonyl, tert-butoxycarbonyl, tetrahydropyranyl or morpholino,

Hydroxyl, cyano, methoxy, methoxycarbonyl, tert-butoxycarbonyl, carboxyl, aminoacetyl, dimethylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, isopropylamino Carbonyl, fluoro-benzylcarbamoyl, cyclopropyl, pyrrolidinyl, piperidino, tetrahydropyranyl, morpholino, morpholinocarbonyl, 2-oxo-1,3-oxazolidine C _1-6 alkoxy group optionally substituted by phthalimido-N-group or hydroxy C _1-6 alkenyloxy group,

^R3 represents H;

R ⁴ represents H;

^R5 represents H; and

R ⁶ represents H.

In another embodiment, the present invention provides a fused pyrrole pyrimidine derivative of formula (I), its tautomeric or stereoisomeric form or a salt thereof:

in

X represents CR ⁵ R ⁶ or NH;

Y ¹ means N;

Y ² and Y ³ represent CR ³ R ⁴ ;

之间的化学键表示单键，exist

The chemical bond between represents a single bond,

Z ³ and Z ⁴ represent CH;

Z ¹ and Z ² represent CH or CR ² respectively;

R ¹ represents 3H-imidazo[4,5-b]pyridyl, benzimidazolyl, pyridyl,

or

1,3-thiazolyl optionally substituted by 1 or 2 methyl groups;

^R represents fluorine, chlorine, bromine, morpholino, piperazinyl, methylpiperazinyl, methyl, trifluoromethyl,

or

C _optionally substituted by hydroxy, cyano, carboxyl, dimethylaminocarbonyl, tetrahydropyranyl, morpholino, morpholinocarbonyl, tetrazolyl or phthalimide-N-yl _-6 alkoxy;

^R3 represents H;

R ⁴ represents H;

^R5 represents H; and

R ⁶ represents H.

In another embodiment, the present invention provides a fused pyrrole pyrimidine derivative of formula (I), its tautomeric or stereoisomeric form or a salt thereof:

in

X represents CR ⁵ R ⁶ or NH;

Y ¹ means N;

Y ² and Y ³ represent CR ³ R ⁴ ;

exist The chemical bond between represents a single bond,

Z ³ and Z ⁴ represent CH;

Z ¹ and Z ² represent CH or CR ² respectively;

In another embodiment, the present invention provides a fused pyrrole pyrimidine derivative of formula (I), its tautomeric or stereoisomeric form or a salt thereof:

in

X represents CR ⁵ R ⁶ or NH;

Y ¹ means N;

Y ² and Y ³ represent CR ³ R ⁴ ;

之间的化学键表示单键，exist

The chemical bond between represents a single bond,

Z ¹ and Z ⁴ represent CH;

Z ² and Z ³ respectively represent CH or CR ² ;

In another embodiment, the present invention provides a fused pyrrole pyrimidine derivative of formula (I), its tautomeric or stereoisomeric form or a salt thereof:

in

X represents CR ⁵ R ⁶ or NH;

Y ¹ means N;

Y ² and Y ³ represent CR ³ R ⁴ ;

之间的化学键表示单键，exist

The chemical bond between represents a single bond,

Z ¹ , Z ³ and Z ⁴ represent CH;

Z ² represents CR ² ;

Preferred compounds of the invention are as follows:

N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-pyridin-3-ylethenol;

N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

6-(acetylamino)-N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

N-{5-[2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridine- 2-yl}acetamide;

2-({5-[2-Hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl }oxy)-N,N-dimethylacetamide;

2-[7-methoxy-8-(tetrahydro-2H-pyran-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl ]-1-pyridin-3-yl vinyl alcohol;

2-[8-(2-Hydroxyethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridine-3- Vinyl alcohol;

({5-[2-Hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy base) acetic acid;

4-({5-[2-Hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl }oxy)butanoic acid;

({5-[2-Hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy base) acetonitrile;

2-[7-methoxy-8-(2H-tetrazol-5-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1 - pyridin-3-yl vinyl alcohol;

2-[7-methoxy-8-(4-morpholin-4-yl-4-oxobutoxy)-2,3-dihydroimidazo[1,2c]quinazolin-5-yl ]-1-pyridin-3-yl vinyl alcohol;

5-[1-Hydroxy-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)vinyl]pyridin-3-ol ;

N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;

6-(acetylamino)-N-(7,9-dimethoxy-8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

N-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;

5-Hydroxy-N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-[(4-methoxybenzyl)oxy ]Nicotinamide;

N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;

5-Hydroxy-N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;

N-{8-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]-2,3-dihydroimidazo[1, 2-c] quinazolin-5-yl} nicotinamide;

N-(7-bromo-8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

6-Amino-N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

1-(1H-benzimidazol-5-yl)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)ethylene alcohol;

2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(2,4-dimethyl-1,3 -thiazol-5-yl) vinyl alcohol;

N-(9-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

N-(8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5carboxamide;

N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1H-benzimidazole-5-carboxamide;

N-(7-fluoro-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

N-(8-chloro-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

6-(acetylamino)-N-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

1-(1H-benzimidazol-5-yl)-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)ethylene alcohol;

N-{5-[1-hydroxyl-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)vinyl]pyridine- 2-yl}acetamide;

6-Methyl-N-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;

1-(1H-benzimidazol-5-yl)-2-[8-(4-methylpiperazin-1-yl)-2,3-dihydroimidazo[1,2-c]quinazoline -5-yl] vinyl alcohol;

N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide;

N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6 - Carboxamide;

N-[7-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1H-benzimidazole-5-carboxamide;

N-(7,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;

N-{5-[2-(7,9-dimethoxy-8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxy Vinyl]pyridin-2-yl}acetamide;

N-{5-[2-(7-bromo-9-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridine- 2-yl}acetamide; and

2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-pyridin-3-ylethenol;

and its tautomeric or stereoisomeric forms, pharmaceutically acceptable salts.

Furthermore, the present invention provides a medicament comprising one of the above compounds and optionally a pharmaceutically acceptable excipient.

Alkyl itself and "alkyl" in alkane, alkoxy, alkanoyl, alkylamino, alkylaminocarbonyl and alkylaminosulfonyl, alkoxycarbonyl, alkoxycarbonylamino and alkanoylamino "Represents a straight or branched chain alkyl group, which usually contains 1-6, preferably 1-4, especially preferably 1-3 carbon atoms, for example and preferably represents methyl, ethyl, propyl, isopropyl, isobutyl Base, tert-butyl, sec-butyl, pentyl, n-hexyl, etc.

Alkylene means a divalent linear or branched saturated hydrocarbon group consisting only of carbon and hydrogen atoms, usually containing 1-6, preferably 1-4, especially preferably 1-3 carbon atoms, enumerating and preferably representing methylene, Ethylene, 2-methylpropylene, butylene, 2-ethylbutylene, etc.

Alkoxy exemplifies and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy, n-hexyloxy and the like.

Alkylamino means alkylamino with one or two (independently selected) alkyl substituents, enumerated and preferably means methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino , n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino , N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamino, N-n-hexyl-N-methylamino, etc.

Alkylaminocarbonyl means bearing one or two (independently selected) alkyl substituents, enumerated and preferably means methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butyl Aminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl -N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylaminocarbonyl, N -n-hexyl-N-methylaminocarbonyl and the like.

Alkylaminosulfonyl means alkylaminosulfonyl with one or two (independently selected) alkyl substituents, enumerated and preferably means methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl , isopropylaminosulfonyl, tert-butylaminosulfonyl, n-pentylaminosulfonyl, n-hexylaminosulfonyl, N,N-dimethylsulfamoyl, N,N-diethylaminosulfonyl, N-ethyl-N-methylsulfamoyl, N-methyl-N-n-propylaminosulfonyl, N-isopropyl-N-n-propylaminosulfonyl, N-tert-butyl-N- Methylaminosulfonyl, N-ethyl-N-n-pentylaminosulfonyl, N-n-hexyl-N-methylaminosulfonyl, and the like.

The alkylsulfonyl group exemplifies and preferably represents methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, n-hexylsulfonyl and the like.

The alkoxycarbonyl group exemplifies and preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl and the like.

Alkoxycarbonylamino enumerates and preferably represents methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino, n-hexyl Oxycarbonylamino, etc.

The alkanoylamino group exemplifies and preferably represents acetamido, ethylcarbonylamino and the like.

Cycloalkyl itself and in cycloalkylamino and cycloalkylcarbonyl means cycloalkyl, usually containing 3-8, preferably 5-7 carbon atoms, enumerated and preferably means cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl, etc.

Aryl itself and "aryl" in arylamino, alkoxyaryl means mono- to tricyclic aromatic carbocyclic groups, usually containing 6-14 carbon atoms, enumerated and preferably means phenyl, naphthyl , Fiki, etc.

Arylamino means arylamino with one or two (independently selected) aryl substituents, enumerated and preferably means phenylamino, diphenylamino, naphthylamino and the like.

Heteroaryl as such and "heteroaryl" in heteroarylamino and heteroarylcarbonyl denotes an aromatic mono- or bicyclic radical, usually containing 5 to 15, preferably 5 or 6 ring atoms, up to 5, Preferably up to 4 heteroatoms selected from S, O and N, enumerated and preferably represented thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiazolyl, pyrazinyl, pyridyl, pyrimidinyl , pyridazinyl, thienyl, indolyl, isoindolyl, benzofuryl, benzothienyl, quinolinyl, isoquinolyl, 1,3 benzodioxol, benzo furyl, benzofuran-2,5-diyl, benzofuran-3,5-diyl, etc.

Heterocycle itself and denotes a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic heterocyclic group, usually containing 4-10, preferably 5-8 ring atoms, up to 3, preferably up to 2, selected from N , O, S, SO and SO2 heteroatoms or heterogroups. The heterocyclic group may be saturated or partially unsaturated, preferably a 5-8 membered monocyclic saturated heterocyclic group with up to two heteroatoms selected from O, N and S, enumerated and preferably tetrahydrofuran-2-yl , pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholino, perhydroazepanyl.

Heterocyclylcarbonyl cites and preferably denotes tetrahydrofuran-2-ylcarbonyl, pyrrolidinyl-2-carbonyl, pyrrolidinyl-3-carbonyl, pyrrolidinecarbonyl, piperidinecarbonyl, morpholinecarbonyl, perhydroazepinecarbonyl.

Halogen and halo represent fluorine, chlorine, bromine and/or iodine.

Furthermore, the present invention provides a medicament comprising one of the compounds as described above and optionally a pharmaceutically acceptable excipient.

embodiment of the invention

Compounds of formula (I) of the present invention can be prepared, but not limited to, by the reactions described below. In certain embodiments, one or more substituents of compounds used as starting materials or intermediates, such as amino, carboxyl and hydroxyl, may advantageously be protected by protecting groups known in the art, examples of which are found in Described in "Protective Groups in Organic Synthesis (Third Edition)" by Greene and Wuts.

The compounds of formula (I) of the present invention can be prepared, but not limited to, by the following methods [A] and [B].

Compound of formula (I-a):

(wherein R ¹ , R ⁵ , R ⁶ , Y ¹ , Y ² , Y ³ , Z ¹ , Z ² , Z ³ and Z ⁴ are the same as defined above) can be, but not limited to, prepared by method A as follows.

method[A]

Compounds of formula (Ia) can be obtained, for example, by combining a compound of formula (II) (wherein Y ¹ , Y ² , Y ³ , Z ¹ , Z ² , Z ³ and Z ⁴ are the same as described above) with a compound of formula (III) (wherein R ¹ , R ⁵ and R ⁶ are the same as above, and L represents a C _1-6 alkyl group).

The reaction can be carried out without or in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, Toluene and xylene; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); Alcohols such as methanol, ethanol, 1-propanol, isopropanol, and t-butanol; water, etc. Optionally, two or more solvents selected from the above may be used in admixture.

The reaction temperature can be optionally set according to the compound to be reacted. The reaction temperature is generally, but not limited to, about 10°C-200°C, preferably about 50°C-160°C, and the reaction can usually be carried out for 10 minutes-48 hours, preferably 30 minutes- 24 hours.

Preparation of intermediates

A compound of formula (II') (wherein Y ¹ , Z ¹ , Z ² , Z ³ and Z ⁴ are the same as defined above, Y ² and Y ³ represent CR ³ R ⁴ or NR ⁴ respectively, connected by a single bond) and The compound of formula (II") (wherein Y ¹ , Z ¹ , Z ² , Z ³ and Z ⁴ are the same as defined above, Y ² and Y ³ respectively represent CH or N, connected by a double bond) can be, but not limited to, Prepared by the following method [Ai]

Method [A-i]

In step 1, the compound of formula (II') (wherein Y ¹ , Z ¹ , Z ² , Z ³ and Z ⁴ are the same as defined above, Y ² and Y ³ respectively represent CR ³ R ⁴ or NR ⁴ , by single bond linkage) can be prepared, for example, by reacting a compound of formula (VI) (wherein Z ¹ , Z ² , Z ³ and Z ⁴ are the same as defined above) with a diaminoalkane derivative, such as ethylenediamine.

The reaction can advantageously be carried out using a suitable dehydrating agent such as SOCl ₂ , POCl ₃ , P ₂ O ₅ , P ₂ S ₅ , CS ₂ and the like.

The reaction can be carried out without or in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, Toluene and xylene etc. Optionally, two or more solvents selected from the above may be used in admixture.

The reaction temperature is generally, but not limited to, about 10°C-200°C, preferably about 50°C-200°C, and the reaction can usually be carried out for 10 minutes-48 hours, preferably 30 minutes-24 hours.

In step 2, the compound of formula (II') (wherein Y ¹ , Z ¹ , Z ² , Z ³ and Z ⁴ are the same as defined above, Y ² and Y ³ respectively represent CH or N, connected by a double bond) It can be obtained, for example, from a compound of formula (II") (wherein Y ¹ , Z ¹ , Z ² , Z ³ and Z ⁴ are the same as defined above, Y ² and Y ³ respectively represent CR ³ R ⁴ or NR ⁴ , connected by a single bond ) is prepared by oxidation using reagents such as _MnO2 , _KMnO4, etc. or by dehydrogenation using palladium/carbon.

The reaction can be carried out in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and Toluene; Dimethylformamide (DMF), Dimethylacetamide (DMAC), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-Dimethyl-2-pyrimidinone (DMI), N-methylpyrrolidone (NMP) and the like. Optionally, two or more solvents selected from the above may be used in admixture.

The reaction temperature is usually, but not limited to, about 0°C-200°C, preferably about 50°C-160°C, and the reaction can be usually carried out for 30 minutes-48 hours, preferably 2 hours-24 hours.

Compounds of formula (VI) are commercially available or can be synthesized by conventional methods.

The compound of formula (III) can be produced, for example, by the following method [A-ii].

Method [A-ii]

The compound of formula (III) (wherein L, R ¹ , R ⁵ and R ⁶ are the same as defined above) can be obtained by making the compound of formula (VII) (wherein R ¹ , R ⁵ and R ⁶ are the same as defined above) with the formula ( VIII) The compound (wherein L is the same as defined above) is prepared by reaction in the presence of a base such as potassium hydride, potassium hexamethyldisilazide and the like.

The reaction can be carried out in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and Toluene; Dimethylformamide (DMF), Dimethylacetamide (DMAC), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-Dimethyl-2-pyrimidinone (DMI), N-methylpyrrolidone (NMP) and the like. Optionally, two or more solvents selected from the above may be used in admixture.

The reaction temperature is usually, but not limited to, about -100°C to 100°C, and the reaction can usually be carried out for 30 minutes to 48 hours, preferably 2 hours to 24 hours.

Alternatively, the compound of formula (III) can be produced, for example, by the following method [A-iii].

Method [A-iii]

The compound of formula (III) (wherein L, R ¹ , R ⁵ and R ⁶ are the same as defined above) can be obtained by making the compound of formula (IX) (wherein R ¹ is the same as defined above, L' is a leaving group, for example Halogen atom, such as chlorine or bromine atom or imidazole) and formula (X) compound (wherein L, R ⁵ and R ⁶ are the same as defined above) or its salt, such as potassium salt reaction preparation.

The reaction can be carried out in the presence of Lewis acids, including magnesium salts, such as magnesium bromide, magnesium chloride, magnesium iodide, magnesium acetate, etc., or in the presence of bases, such as n-butyllithium, sec-butyllithium, and the like. The reaction can be carried out in a solvent including ethers such as diethyl ether, isopropyl ether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene, and the like. Optionally, two or more solvents selected from the above may be mixed and used.

The preparation of formula (I-b) compound:

(wherein R ¹ , R ⁵ , R ⁶ , Y ¹ , Y ² , Y ³ , Z ¹ , Z ² , Z ³ and Z ⁴ are the same as defined above) can be, but not limited to, prepared by method B as follows.

method [B]

Compounds of formula (Ib) can be obtained, for example, by combining compounds of formula (IV) (wherein Y ¹ , Y ² , Y ³ , Z ¹ , Z ² , Z ³ and Z ⁴ are as defined above) with compounds of formula (V) (wherein R ¹ is the same as defined above, and L" is a leaving group such as hydroxyl; a halogen atom such as chlorine, bromine or iodine atom; imidazole or wherein R ¹ is the same as defined above) prepared by reaction. In the case where L" is hydroxyl, the reaction is advantageously carried out by using a coupling reagent such as benzotriazol-1-yl-oxy-tripyrrolidone phosphonium-hexafluorophosphate (PyBOP), 1,1'-carbonyl-linked (1,3-imidazole) (CDI), 1,1'-carbonyl (1,2,4-triazole) (CDT) and so on.

In L" is a halogen atom, imidazole or In the case of , the reaction can be advantageously carried out in the presence of a base including, for example, pyridine, triethylamine, and N,N-diisopropylethylamine, diethylaniline, diethylaniline, and the like.

The reaction can be carried out without or in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, Toluene and xylene; nitriles, such as ethylamine; amides, such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea , such as 1,3-dimethyl-2-imidazolidinone (DMI); sulfoxides, such as dimethyl sulfoxide (DMSO) and the like. Optionally, two or more solvents selected from the above may be used in admixture.

The reaction temperature is usually, but not limited to, about 40°C-200°C, preferably about 20°C-180°C, and the reaction can usually be carried out for 30 minutes-48 hours, preferably 2 hours-12 hours.

Intermediate preparation

The compound of formula (IV) can be, but not limited to, prepared by the following method [B-i]:

Method [B-i]

The compound of formula (IV) (wherein Y ¹ , Y ² , Y ³ , Z ¹ , Z ² , Z ³ and Z ⁴ are the same as defined above) can be obtained by making the compound of formula (II) (wherein Y ¹ , Y ² , Y ³ , Z ¹ , Z ² , Z ³ and Z ⁴ are the same as defined above) prepared by reacting with cyanogen halide, such as cyanogen bromide.

The reaction can be carried out in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and Toluene; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert butanol etc. Optionally, two or more solvents selected from the above may be used in admixture.

The reaction temperature is usually, but not limited to, about -10°C to 200°C, and the reaction can usually be carried out for 30 minutes to 48 hours, preferably 1 hour to 24 hours.

The compound of formula (II) (wherein Y ¹ , Y ² , Y ³ , Z ¹ , Z ² , Z ³ and Z ⁴ are the same as defined above) can be obtained by the same method described in method [Ai].

Compounds of formula (VII), (VIII), (IX) and (X) are commercially available or can be synthesized by conventional methods.

When the compound represented by formula (I) or its salt has an asymmetric carbon in the structure, its optically active compound and racemic mixture are also included in the scope of the present invention.

Typical salts of the compound represented by formula (I) include salts prepared by reacting the compound of the present invention with an inorganic or organic acid, or an organic or inorganic base, which are called acid addition salts and base addition salts, respectively.

Those that form acid addition salts include inorganic acids such as, but not limited to, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc., organic acids such as, but not limited to, p-toluenesulfonic acid, methanesulfonic acid, Oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, acetic acid, etc.

Base addition salts include inorganic bases such as, but not limited to, ammonium hydroxide, non-metal hydroxides, alkaline earth metal hydroxides, carbonates, bicarbonates, etc., and organic bases such as, but not limited to, Salts of ethanolamine, triethylamine, tris(hydroxymethyl)aminomethane, etc. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like.

Depending on the substituent, the compounds of the present invention or their salts may be modified to form lower alkyl esters or other known esters; and/or hydrates or other solvates, these esters, hydrates and solvates are included in the scope of the present invention within range.

The compounds of the present invention can be administered in oral forms such as, but not limited to, normal and enteric-coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solids and liquids Aerosols and lotions. They can also be administered in parenteral forms known to those skilled in the pharmaceutical arts, such as, but not limited to, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like. Compounds of this invention 12 may be administered in intranasal form, via topical application of suitable intranasal vehicles, or via the use of transdermal delivery systems known to those skilled in the art.

Dosage regimes for the compounds of this invention are selected by those of ordinary skill in the art based on a variety of factors including, but not limited to, the age, weight, sex, and clinical symptoms of the patient, the severity of the symptoms being treated, the route of administration, the patient's metabolism, and The level of secretory function, the dosage form used, the specific compound used and its salts.

The compounds of the invention are preferably formulated for administration with one or more pharmaceutically acceptable excipients. Excipients are inert substances such as, but not limited to, carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating materials.

Another embodiment of the invention is a pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically acceptable excipients which are compatible with the other ingredients of the formulation and which are not harmful to the patient. The pharmaceutical formulations of the present invention are prepared by mixing a therapeutically effective amount of a compound of the present invention with one or more pharmaceutically acceptable excipients. In preparing the compositions of the present invention, the active ingredient may be admixed with a diluent, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. The carrier may serve as a diluent, which may be a solid, semi-solid or liquid material used as a vehicle, or it may be in the form of a tablet, pill, powder, lozenge, elixir, suspension, emulsion, solution, syrup, aerosol, Ointments, soft and hard gelatine capsules, suppositories, sterile injectable solutions and sterile packaged powders containing, for example, up to 10% by weight of the active ingredient.

For oral administration, the active ingredient can be mixed with oral and nontoxic pharmaceutically acceptable carriers such as, but not limited to, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, Calcium sulfate, methylcellulose, etc., optional disintegrants, such as, but not limited to, cornstarch, methylcellulose, agar, bentonite, xanthan gum, alginic acid, etc.; optional binders, such as , but not limited to, capsules, natural sugars, β-lactose, corn sweeteners, natural and synthetic gums, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc.; any Selected lubricants, such as, but not limited to, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.

In powder forms, the carrier is a finely divided solid, which is in admixture with the finely divided active ingredient. The active ingredient can be mixed with a carrier having binding properties in suitable proportions and compressed in the shape and size desired to produce tablets. Powders and tablets preferably contain from about 1 to about 99% by weight of active ingredient, which are novel compositions of the present invention. Suitable solid carriers are carboxymethylcellulose magnesium, low melting wax and cocoa butter.

Sterile liquid preparations include suspensions, emulsions, syrups and elixirs in which the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier such as sterile water, a sterile organic solvent or a mixture of sterile water and a sterile organic solvent.

The active ingredient can also be dissolved in suitable organic solvents, for example aqueous propylene glycol. Other compositions may be obtained by dispersing the finely divided active ingredient in an aqueous solution of starch or sodium carboxymethylcellulose or a suitable oil.

The formulations may be in unit dosage form, which is a physically discrete unit containing unit dosages, suitable for human or other mammalian use. The unit dosage form can be a capsule or tablet, or a plurality of capsules or tablets, a "unit dosage" being a predetermined quantity of an active compound of this invention calculated to produce the desired therapeutic effect, in admixture with one or more excipients. The amount of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 mg depending on the particular treatment involved.

Typical oral dosages of the present invention will be about 0.01 mg/kg/day to about 100 mg/kg/day, preferably 0.1 mg/kg/day to 30 mg/kg/day, most preferably about 0.5 mg/kg/day for the indicated effects. mg/kg/day to about 10 mg/kg/day. In the case of parenteral administration, it generally proves advantageous to administer about 0.001-100 mg/kg/day, preferably 0.01 mg/kg/day-1 mg/kg/day. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, 2, 3 or more times per day. Where delivery is in a transdermal form, the administration will, of course, be continuous.

Example

The present invention will be described in detail below in the form of examples, but they should not be construed as bounds and scope of the present invention.

In the following examples, all quantitative data refer to percentages by weight, if not stated otherwise.

¹ H NMR spectra were recorded on a Bruker DRX-300 (300 MHz for 1H) spectrometer or Brucker 500 UltraShieledTM (500 MHz for 1H), chemical shifts are reported in parts per million (ppm), using 0 ppm tetramethylsilane (TMS) as Internal standard. Coupling constants are in Hertz and the abbreviations s, d, t, q, m, and br refer to singlet, doublet, triplet, quartet, multiplet, and broad, respectively. Mass determination was performed with MAT95 (Finnigan MAT).

Liquid chromatography-mass spectrometry (LC-MS) data was recorded with a Micromass Platform LC equipped with a Shimadzu Phenomenex ODS column (4.6mm×30mm) washed with a mixture of acetonitrile-water (9:1-1:9) at 1ml/flow rate. Mass spectra were obtained by electron spray (ES) ion technique (Micromass Platform LC), TLC was carried out on pre-coated silica gel plates (Merck silicagel 60F-254), silica gel (WAKO-gel C-200 (75-150 μm)) was used on all column chromatographic separations. All chemicals are reagent grade and supplied by Sigma-Aldrich, Wakopuechemical industries, Ltd., Tokyo kasei kogyo Co., Ltd., Nacalaitesque, Inc., Watanabe Chemical Ind. Ltd., Maybridge plc, Lancaster Synthesis Ltd., Merck KgaA, Purchased by Kanto Chemical Co., Ltd.

The effects of the compounds of the present invention were examined by the following test.

[Determination of Compound IC50 Values in PI3Kγ Kinase Assay]

Chemical Substances and Test Materials

Phosphoinositide (PtdIns) and phosphatidylserine (PtdSer) were purchased from DOOSANSERDARY RESEARCH LABORATORIES (Toronto, Canada). Recombinant human PI3Kγ (full-length human PI3Kp110γ expressed in S. frugiperda9 insect cells with a His6-tag fused at the C-terminus) was purchased from ALEXIS BIOCHEMICALS (#201-055-C010; San Diego, CA). [γ ³³ P]ATP and unlabeled ATP were obtained from AMERSHAMPHARMACIA BIOTECH (Buckinghamshire, UK) and ROCHE DIAGNOSTICS (Mannheim, Germany), respectively. Scintillation Cocktail and MicroScint PS ^™ were purchased from PACKARD (Meriden, CT), Maxisorp ^™ Plates were purchased from NALGE NUNC INTERNATIONAL K.K. (Tokyo, Japan), gaseous other chemicals not otherwise specified were from WAKO PURE CHEMICALS (Osaka, Japan) .

solid phase lipid kinase assay

To assess the inhibitory effect of compounds on PI3Kγ, Maxisorp ^™ plates were coated with 50 μl/well of a solution containing 50 μg/ml PtdIns and 50 μg/ml PtdSer dissolved in chloroform:ethanol (3:7). Plates were then placed in a fume hood for at least 2 hours to air dry, and the reaction was performed by mixing 25 μl/well assay buffer 2× (100 mM M OPSO/NaOH, 0.2 M NaCl, pH 7.0, 8 mM MgCl ₂ , 2mg/ml BSA (fatty acid free)) and 50ng/well PI3Kγ establishment, added 10x test compound in 2% DMSO. Reactions were performed by adding 20 μl/well of ATP mix (final 10 μM ATP; 0.05 μCi/well [γ ³³ P]ATP). After incubation for 2 hours at RT, the reaction was stopped by adding 50 μl/well of stop solution (50 mM EDTA, pH 8.0). Plates were then washed twice with Tris-buffered saline (TBS, pH 7.4), MicroScint PS ^™ (PACKARD) scintillation hydrate was added at 100 μl/well, and radioactivity was counted using a TopCount ^™ (PACKARD) scintillation counter.

The percent inhibition was calculated for each compound concentration and IC50 values were determined from the inhibition curves.

[Isozyme selectivity in PI3K]

{Determination of Compound IC50 Values in PI3Kβ Kinase Assay}

Recombinant baculoviruses of PI3Kβp110β and GST-p85α were obtained from Dr. Katada (University of Tokyo), and recombinant PI3K heterocomplexes of p110β and GST-p85α were synthesized in insect cells according to the manufacturer's instructions (Pharmingen, San Diego, CA). Expressed and purified with a glutathione affinity column. Kinase assays for PI3Kβ were prepared in a similar manner as described in the section [Determination of IC50 values of compounds in PI3Kγ kinase assays].

[Selectivity test for other kinases]

The kinase properties of compounds are determined by using several kinase assays, such as the Syk kinase assay.

{for selective Syk tyrosine kinase inhibition assay}

(1) Syk protein preparation

The cDNA fragment encoding the open reading frame of human Syk was cloned from the total RNA of human Burkitt's lymphoma B cell line, Raji (American Type Culture Collection) by RT-PCR method. The cDNA fragment was inserted into pAcG2T (Pharmingen, San Diego, CA) to constitute the non-baculovirus transfer factor. This factor was then used together with linearized baculovirus (BaculoGold™, Pharmingen) to transfect Sf21 cells (Invitrogen, San Diego, CA).

The resulting recombinant baculoviruses were cloned and amplified in Sf21 cells. Sf21 cells were infected with this amplified high titer virus to produce a chimeric protein of Syk kinase fused to glutathione-S-transferase (GST).

The obtained GST-Syk was purified with a glutathione column (AmershamPharmacia Biotech AB, Uppsala, Sweden) according to the manufacturer's instructions, and the purity of the protein was more than 90%, as confirmed by SDS-PAGE.

(2) Synthesis of peptides

Subsequently, a peptide fragment comprising 30 residues including two tyrosine residues, KISDFGLSKALRADENYYKAQTHGKWPVKW was synthesized with a peptide synthesizer, and the N-terminus of the fragment was then biotin-labeled to obtain a biotin-labeled activated cyclic peptide (AL) .

(3) Measurement of Syk tyrosine kinase activity

All reagents were diluted with Syk kinase assay buffer (50 mM Tris-HCl (pH 8.0), 10 mM MgCl ₂ , 0.1 mM Na ₃ VO ₄ , 0.1% BSA, 1 mM DTT). A mixture (35 μl) comprising 3.2 μg GST-Syk and 0.5 μg AL was first added to each well of a 96-well plate, followed by the addition of 5 μl of the test compound in the presence of 2.5% dimethyl sulfoxide (DMSO) to each well 300 μM ATP (10 μl) was added to the mixture to initiate the kinase reaction, and the final reaction mixture (50 μl) consisted of 0.65 nM GST-Syk, 3 μM AL, 30 μM ATP, test compound, 0.25% DMSO and Syk kinase assay buffer.

The mixture was incubated at room temperature (RT) for 1 hour, and the reaction was stopped by adding 120 μl of stop buffer (50 mM Tris-HCl (pH 8.0), 10 mM EDTA, 500 mM NaCl, 0.1% BSA). The mixture was transferred to a streptavidin-coated plate and incubated at room temperature for 30 minutes to bind biotin-AL to the plate. After washing 3 times with Tris-buffered saline (TBS) (50mM Tris-HCl (pH8.0), 138mM NaCl, 2.7mM KCl) containing 0.05% Tween-20, add 50mM Tris-HCl (pH8.0) , 138mM NaCl, 2.7mM KCl, 1% BSA, 60ng/ml anti-phosphotyrosine monoclonal antibody labeled with europium in advance with Amersham Pharmacia's device, 100μl antibody solution composed of 4G10 (Upstate Biotechnology), incubated at room temperature 60 minutes. After washing, 100 μl enhancement solution (Amersham Pharmacia Biotech) was added and time-resolved fluorescence was measured with a multilabel counter ARVO (Wallac Oy, Finland) with excitation at 340 nm and emission at 615 nm with a delay of 400 μs and a window of 400 μs.

[Measurement of compound IC50 value in peroxide generation by human peripheral mononuclear cells]

Blood (100ml/donor) was collected from healthy human volunteers by venipuncture with a 50ml syringe containing 50 units of heparin, by adding 1% (w/v) dextran and 0.45% (w/v) glucose at room temperature. Incubate for 30 minutes to remove red blood cells. After centrifugation at 350xg for 10 min, the cell pellet was suspended in 10 ml of PBS, and the cell suspension was in 20 ml of 60% and 20 ml of 80% Percoll (Amersham Pharmacia) in 50 ml tube (#2335-050, Iwaki, Japan) in PBS. Biotech, Sweden) gradually layered on the gradient. After centrifugation at 400xg for 30 minutes at room temperature, peripheral segmented nuclei (PMNs) were obtained from the phase interface of 60% and 80% Percoll. After washing twice in PBS, the PMNs were suspended at a density of 10 ⁷ cells/ml in Hank's Balanced Salt Solution (HBSS: Nissui, Japan) enhanced with 10 mM Na-Hepes (pH 7.6), 0.1% BSA , kept on ice until further use.

Inhibition of test compounds on formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide generation, PMN (2×10 ⁵ cells/well) in HBSS, 10 mM Na-Hepes ( pH 7.6), 0.1% BSA in 96-well clear bottom black plates (Cat#3904, Costar), pretreated with 3-aminobenzenedihydrazide (1 μg/well; Sigma) and test compound for 10 min at 37°C . fMLP peptide (Cat. #4066; Peptide Institute Inc, Japan) was prepared at 10 μM in the same buffer, prepared in polypropylene plates (Cat. #3365, Coster). Chemiluminescence (CL) was measured 15 minutes after stimulation with 1 μM fMLP with FDSS-6000 (Hamamatsu Photonics). The percent inhibition at each compound concentration was calculated based on the first peak of CL approximately 1 min after the addition of the stimulus, and IC50 values were determined from the inhibition curves.

To modulate the stimulating effects of zymosan (OZ) and phorbol 12-myristate 13-acetate (PMA), zymosan A (Sigma) was suspended in HBSS at a concentration of 1 mg/ml and harvested from humans The serum was incubated at a final concentration of 9-80% at 37 °C for 30 min to opsonize the zymosan, followed by centrifugation at 500 x g for 10 min at 4 °C. The sediment was then washed twice with HBSS and finally suspended in HBSS to a concentration of 1-10 mg/ml. Opsonized zymosan (OZ) was used for stimulation at 5 mg/ml. Phorbol 12-myristate 13-acetate (PMA) was initially dissolved in DMSO at a concentration of 0.1 mg/ml for use as a stock solution and stored frozen at -20°C. PMA solutions were prepared from stock solutions by further dilution in HBSS to a concentration of 100 ng/ml. PMNs (2×10 ⁵ cells/well) were seeded in 96-well white plates (Packard) in HBSS, 10 mM Na-Hepes (pH 7.6), 0.1% BSA, and treated with 3-aminobenzenedihydrazide (1 μg/well; Sigma) and test compounds were pretreated at 37°C for 10 minutes. CL was measured with an Arvo counter (Wallac) 30 min after stimulation with OZ or PMA. The percent inhibition at each compound concentration was calculated and IC50 values were determined from the inhibition curves.

[Determination of IC50 values of compounds in elastase release from human peripheral monocytes]

To test compounds for inhibition of elastase release, PMNs (5×10 ⁵ cells/well) were seeded in 96-well plates in HBSS enhanced with 10 mM Na-Hepes (pH 7.6), 0.1% BSA, and cells were Relaxin B (0.1 µg/well; Nakarai, Japan) and test compound were pretreated at 37°C for 10 minutes at 90 µl/well. Cells were stimulated with 1 μM fMLP for 15 minutes at 37° C., and supernatants (40 μl/well) were collected into 384-well black plates (Packard) to measure elastase activity. . Fluorescent-based elastase activity was initiated by adding 10 μl of 0.5 mM Suc-Ala-Ala-Ala-MCA (Cat. #3133v; Peptide Institute Inc, Japan) in a 384-well plate at room temperature. Fluorescence emission was measured at 460 nm (λex, 360 nm) for 120 minutes with a Wallac-Arvo counter (Perkin Elmer, Boston, MA) fluorescent plate reader. IC50 values of compounds were determined at the initial rate of reaction.

[Determination of IC50 values of compounds in chemotaxis assay using human PMN]

Freshly prepared PMNs (1.1×10 ⁷ cells/ml) were plated together with compounds in polypropylene 96-well plates (Cat.#3365, Coster) in HBSS enhanced with 10 mM Na-Hepes (pH 7.6), 0.1% BSA cultivated in. Cells (100 μl) were incubated with test compound or carrier for 30 minutes, transferred to Multiwell insert (Cat. #351183; Falcon) 24w plate, added FMLP (10 nM, 0.5 ml) in the lower chamber of the plate, and placed in a CO ₂ incubator at 37 Chemotaxis was measured for 1 hour at °C. Migrated cells were counted with a FACScan (Becton Dickinson, Franklin Lakes, NJ). The percent inhibition at each compound concentration was calculated and IC50 values were determined from the inhibition curves.

[Measurement of compound IC50 value in chemotaxis assay with transfectants]

(1) cell

Human CCR3-transformed L1.2 cells were used. Human CCR3-expressing LI.2 stable transformants were determined by electroporation referring to the method described in J. Exp. Med. 183: 2437-2448, 1996 . Human CCR3-transformed L1.2 cells were maintained in RPMI-1640 enhanced with 10% FCS, 100 units/ml penicillin G and 100 μg/ml streptomycin and 0.4 mg/ml Geneticin. One day before the chemotaxis assay, cells were pretreated with 5 mM sodium butyrate containing medium (5×10 ⁵ cells/ml) for 20-24 hours to increase the expression of CCR3.

(2) Chemotaxis test

Suspend the butyrate-pretreated cells at a density of 1.1×107cells/ml in chemotaxis buffer (Hanks solution Cat.#05906 Nissui, 20mM HEPES pH7.6, 0.1% human serum albumin Cat.#A-1887 Sigma). A mixture of 90 µl of the cell suspension and 10 µl of the compound solution (10-fold concentration of the final concentration) diluted with a chemotaxis buffer was pre-incubated at 37°C for 10 minutes. The mixture of cells and compounds was added to the upper chamber of a 24-well chemotaxis chamber (Transwell ^(TM) , Cat. #3421, Costar, pore size; 5 [mu]m). 0.5 ml of 10 nM human recombinant eotaxin (Cat. #23209, Genzyme Techne) diluted with chemotaxis buffer was added to the lower chamber of the chemotaxis plate. Chemotaxis was then performed at 37°C for 4 hours in a CO ₂ incubator, and after 4 hours of incubation, migrated cells were counted with FACScan (Becton Dickinson). The percent inhibition at each compound concentration was calculated and IC50 values were determined from the inhibition curves.

[Mouse fMLP-induced pleurisy model]

Seven-week-old BALB/c female mice were divided into 3 groups, non-treatment group, vehicle group and treatment group. The mice in the treatment group were first injected intravenously with different doses of the compound of the present invention, and the mice in the vehicle group were injected with a vehicle containing 10% Cremophor EL (Nacalai Tesque) in saline. Three minutes after treatment, 1 mg/mouse fMLP in 3.3% DMSO in PBS was administered intrapleurally to vehicle and treatment group mice. Four hours after fMLP, mice were sacrificed and pleural fluid was collected by filling the pleural cavity twice with 2 ml PBS. Count the total cells per ml of pleural fluid with a hemocytometer. Cellular differentiation of pleural fluid was determined by counting a minimum of 200 cells from Giemsa's-stained cytospin slide preparations. Statistical analysis was performed by Student's t-test for paired data or by Dunnett's Post test for change, using GraphPad PRISM for Windows, version 2.01.

For practical reasons, the compounds are grouped into certain active classes as follows:

In vitro IC ₅₀ ＝A(=or<)0.1μM<B(=or<)0.5μM<C(=or<)2μM<D

The compounds of the invention also show strong activity in in vivo tests.

In the following table (dec.) represents the decomposition.

Example 1-1:

Z)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridyl)ethanol

(1) Methyl 3-oxo-3-(3-pyridyl)propionate

A 0.5M solution of sodium hexamethyldisilazide in toluene (22ml, 11mmol) was mixed with tetrahydrofuran (5ml), and the mixture was cooled to -78°C. To the cooled (-78°C) mixture was added dropwise a solution of 3-acetylpyridine (1.0 g, 8.26 mmol) in tetrahydrofuran (5 ml). The mixture was warmed to room temperature and stirred for 3 hours. The mixture was cooled to -78°C, followed by the dropwise addition of dimethyl carbonate (1.2ml, 14.3mmol). The resulting solution was allowed to warm to room temperature and stirred overnight. The reaction solution was quenched by adding aqueous 1N hydrochloric acid solution, and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate, 1/1) to give methyl 3-oxo-3-(3-pyridyl)propanoate (1.0 g, 68% yield) as an oil thing.

(2) 2-(4,5-dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline:

Add ethylenediamine (7.9g, 131mmol) to 2-amino-4,5-dimethoxybenzonitrile (5.0g, 28mmol) at room temperature, warm the resulting solution to 40°C, add a catalytic amount of phosphorus pentasulfide (50mg ). The mixture was heated to 80-90°C and stirring was continued overnight. The reaction mixture was diluted with water and the resulting precipitate was collected by filtration to give 2-(4,5-dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline (5.1 g, 82%) as a solid.

(3) (-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridyl)ethylene alcohol

2-(4,5-dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline (0.15g, 0.68mmol) and methyl-3-oxo-3(3-pyridine base) propionate (0.20 g, 1.12 mmol) was stirred at 155 for 1 hour. The reaction mixture was purified by column chromatography on silica gel (dichloromethane/methanol, 25/1) to give (Z)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2- c] quinazolin-5-yl)-1-(3-pyridyl)vinyl alcohol (66.9 mg, 28%) yellow solid.

Melting point: 275°C

Mass spectrum: 351

In vitro PI3K-β inhibitory activity: C

In vitro PI3K-γ inhibitory activity: A

¹ H-NMR (500MHz, DMSO-d ₆ ): δ3.79 (3H, s), 3.88 (3H, s), 3.98-4.08 (4H, m),

5.63 (1H, s), 7.13 (1H, s), 7.24 (1H, s), 7.50 (1H, dd, J=4.7, 7.8Hz), 8.27 (1H, dt, J=1.6, 7.8Hz), 8.67 (1H, dd, J=1.6, 4.7 Hz), 9.13 (1H, d, J=1.6 Hz), 13.9 (1H, bs).

Embodiment 1-2:

(Z)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridyl)-ethylene Alcohol hydrochloride

To (Z)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridyl)ethylene To a solution of the alcohol (16.8mg, 0.05mmol) in dioxane (15ml) was added a solution containing 6N HCl (0.05ml) at room temperature. After stirring for 30 minutes, the mixture was dried under reduced pressure to obtain (Z)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl) - 1-(3-pyridyl)vinyl alcohol hydrochloride (18.5 mg, quantitative) yellow solid.

Melting point: >300°C

Mass spectrum: 351

In vitro PI3K-β inhibitory activity: C

In vitro PI3K-γ inhibitory activity: A

¹ H-NMR (500MHz, DMSO-d ₆ ): δ3.88(3H, s), 4.00(3H, s), 4.22(2H, t, J=9.1Hz), 4.55(2H, t, J=9.1 Hz), 6.21(1H, s), 7.60(1H, s), 7.66(1H, dd, J=4.7, 8.2Hz), 7.90(1H, s), 8.47(1H, d, J=8.2Hz), 8.79 (1H, d, J=4.7Hz), 9.28 (1H, s), 14.9 (1H, bs).

Embodiment 1-3:

2-[7-methoxy-8-(methoxymethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl-1-pyridin-3-yl vinyl alcohol

(1) 4-formyl-2-methoxy-3-nitrophenyl acetate

Using the method described in US4287341 or J.Chem.Soc.376 (1948), 5.00g of vanillin acetate was used to obtain 4.54g of the title compound as a yellow solid, with a yield of 73.6%.

H-NMR (500MHz, DMSO-d ₆ ) δ: 2.40(s 3H), 3.87(s 3H), 7.75(d 1H J=8.4Hz), 7.94(d 1H J=8.4Hz), 9.90(s 1H)

(2) 4-Hydroxy-3-methoxy-2-nitrobenzaldehyde

A mixture of 4.54 g (19.0 mmol) of 4-formyl-2-methoxy-3-nitrophenyl acetate and 5.24 g (37.9 mmol) of potassium carbonate in 40 mL of methanol was stirred at room temperature for 2 hours. The reaction mixture was poured into water, acidified with 1N hydrochloric acid solution, and extracted with AcOEt. The organic layer was washed with brine, dried over _MgSO4 , filtered and the solvent was evaporated. The residue was washed with cyclohexane to obtain 3.60 g of the title compound as a white solid, with a yield of 96.3%.

(3) 4-Hydroxy-3-methoxy-2-nitrobenzonitrile

Add 22.4 g (88.2 mmol) of iodine to a mixture of 14.5 g (73.5 mmol) of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde in 150 mL of 28% ammonia solution and 15 mL of tetrahydrofuran, and stir overnight at room temperature . The reaction mixture was concentrated in vacuo, the residue was acidified with 2N HCl solution and extracted with ether. The organic layer was washed with brine, dried over _MgSO4 , filtered and the solvent was evaporated. The residue was washed with diisopropyl ether to obtain 12.1 g of the title compound as a brown solid. Yield 84.5%.

(4) 3-methoxy-4-(methoxymethoxy)-2-nitrobenzonitrile

Add 1.00g of 4-hydroxy-3-methoxy-2-nitrobenzonitrile, 0.47mL (6.18mmol) of chloromethyl methyl ether and 3.56g (25.8mmol) of potassium carbonate in N,N-dimethylformaldehyde The mixture in amide 10 mL was stirred at 50°C for 2 hours. The reaction mixture was poured into water and extracted with ether. The organic layer was washed with brine, dried, filtered and the solvent was evaporated. The title compound was obtained by silica gel chromatography (cyclohexane/AcOEt=4/1) as a colorless solid (1.03 g, yield 83.5%).

(5) 2-Amino-3-methoxy-4-(methoxymethoxy)benzonitrile

Add a solution of 6.00 g (25.2 mmol) of 3-methoxy-4-(methoxymethoxy)-2-nitrobenzonitrile in 50 mL of ethanol to 6.00 g of 5% palladium/activated carbon under an argon atmosphere , stirred at room temperature under hydrogen for 8 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo, and 2.83 g of the title compound was obtained as a white solid by silica gel chromatography (cyclohexane/AcOEt=4/1), yield 53.9%.

(6) [6-(4,5-Dihydro-1H-imidazol-2-yl)-2-methoxy-3-(methoxymethoxy)phenyl]amine

A solution of 2-amino-3-methoxy-4-(methoxymethoxy)benzonitrile 475mg (2.28mmol) and phosphorus pentasulfide 25.4mg (0.11mmol) in ethylenediamine 2.75g was heated at 120°C Stir overnight. The reaction mixture was cooled to room temperature, poured into water, and the precipitate was collected and washed with water to obtain 293 mg of the title compound as a white solid, with a yield of 51.1%.

(7) Ethyl 3-oxo-3-(pyridin-3-yl)propionate

To a suspension of 5.00 g (40.6 mmol) of nicotinic acid in 50 mL of tetrahydrofuran was added 9.76 g (60.9 mmol) of carbonyl biimidazole at 5° C., followed by stirring at room temperature for 1 hour. In another flask, a suspension of MgCl ₂ 4.64 g (48.7 mmol) and ethyl malonate potassium salt 10.37 g (60.92 mmol) in tetrahydrofuran 50 mL was stirred at 50° C. for 4 hours. To this suspension was added the above imidazole solution at room temperature, followed by stirring for 12 hours. The reaction was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with brine, dried over _MgSO4 , filtered and the solvent was evaporated. Silica gel chromatography (cyclohexane/AcOEt=2/1) gave 3.89 g of the title compound as a light yellow oil with a yield of 49.5%.

(8) 2-[7-methoxy-8-(methoxymethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridine -3-yl vinyl alcohol

[6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(methoxymethoxy)phenyl]amine 1.31g (5.20mmol) and 3- A solution of 1.00 g (5.20 mmol) of ethyl oxo-3-(pyridin-3-yl) propionate in 30 mL of toluene was refluxed overnight, the precipitate was collected and washed with ether to obtain 1.52 g of the title compound as a light yellow solid, yield 76.9% .

Melting point: 215-216°C

Mass spectrum: 381

In vitro PI3K-β inhibitory activity:

In vitro PI3K-γ inhibitory activity: B

H-NMR (500MHz, CDCl ₃ ) δ: 3.54(s 3H), 3.95(t 2H J=9.5 Hz), 4.08(s 3H), 4.22(t 2H J=9.5Hz), 5.30(s 2H), 5.38 (s 1H), 6.98 (d 1H J = 8.8Hz), 7.37 (dd 1H J = 8.0Hz, 4.9Hz), 7.64 (d 1H J = 8.8Hz), 8.21 (dt 1H J = 8.0Hz, 1.7Hz), 8.67 (dd 1H J = 4.9 Hz, 1.7 Hz), 9.09 (d 1H J = 1.7 Hz), 13.75 (s 1H).

Embodiment 1-4:

5-(2-Hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol hydrochloride

2-[7-Methoxy-8-(methoxymethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]- A suspension of 1.52 g (4.00 mmol) of 1-pyridin-3-ylvinyl alcohol (Example 1-3) in 30 mL of 1,4-dioxane and 0.3 mL of water was stirred overnight at room temperature. The reaction mixture was diluted with diethyl ether, and the precipitate was collected and washed with diethyl ether to obtain 1.23 g of the title compound as a yellow solid, with a yield of 82.4%.

Melting point: 245°C

Mass spectrum: 337

In vitro PI3K-β inhibitory activity: C

In vitro PI3K-γ inhibitory activity: A

H-NMR (500MHz, DMSO-d ₆ ) δ: 3.97(s 3H), 4.22(dd 2H J=12.3Hz, 9.0Hz), 4.43(dd 2H J=12.3Hz, J=9.0Hz), 6.17(s 1H), 7.10 (d 1H J = 9.0Hz), 7.71 (dd 1H J = 7.7Hz, 4.7Hz), 7.98 (d 1H J = 9.0Hz), 8.57 (brd 1H J = 7.7Hz), 8.82 (dd 1H J =4.7Hz, 1.4Hz), 9.34(d1HJ=1.4Hz), 11.79(s1H), 4.60(s1H)

Embodiment 1-5:

4-[5-(2-Hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2c]quinazolin-8-yl]oxy } methyl butyrate

5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazoline-8- Alcohol hydrochloride (Example 1-4) 50.4mg (0.14mmol), methyl chlorobutyrate 22.2mg (0.16mmmol) and potassium carbonate 186.9mg (1.35mmmol) in N, N-dimethylformamide 1mL mixture for 4 hours. The reaction mixture was poured into water and extracted with dichloroethane. The organic layer was washed with brine, dried over _MgSO4 , filtered and the solvent was evaporated. The residue was washed with diethyl ether to obtain 35.0 mg of the title compound as a yellow solid, with a yield of 59.3%.

Melting point: 199-200°C

Mass spectrum: 437

In vitro PI3K-β inhibitory activity: C

In vitro PI3K-γ inhibitory activity: A

H-NMR (500MHz, CDCl ₃ ) δ: 2.20(quint 2H J=7.1Hz), 2.58(t 2HJ=7.09Hz), 3.71(s 3H), 3.94(t 2H J=9.5Hz), 4.06( s 3H), 4.15(t 2HJ=7.1Hz), 4.21(t 2H J=9.5Hz), 5.38(s 1H), 6.76(d 1H J=8.8Hz), 7.37(dd 1H J=8.2Hz, 5.2Hz ), 7.65(d 1H J=8.8Hz), 8.21(dtJ=8.2Hz, 2.1Hz), 8.67(d 1H J=5.2Hz), 9.09(s 1H), 13.70(s 1H)

Embodiment 1-6:

Example 3-4; 4-[5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazole Lin-8-yl]oxy}butanoic acid

4-{[5-(2-Hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydro-imidazo[1,2-c]quinazole was stirred at room temperature A solution of 20.0 mg (0.05 mmol) of methyl phen-8-yl]oxy}butanoate (Example 1-5) in 0.1 mL of IN LiOH solution and 1.0 mL of ethanol overnight. The reaction mixture was neutralized with 1N HCl solution, concentrated in vacuo, the residue was triturated with water, and the precipitate was collected to obtain the title compound as a white solid (10.0 mg, yield 51.7%).

Melting point: 257-258°C

Mass spectrum: 423

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: A

H-NMR (500MHz, DMSO-d ₆ ) δ: 2.02 (quint 2H J = 6.2Hz), 2.45 (t 2HJ = 6.2Hz), 3.94 (s 3H), 3.98 (brt 2H J = 8.5Hz), 4.06(brt 2HJ=8.5Hz), 4.14(t 2H J=6.2Hz), 5.67(s 1H), 6.97(d 1H J=8.7Hz), 7.49(dd 1H J=8.2Hz, 4.4Hz), 7.57( d 1H J=8.7Hz), 8.29(d 1H J=8.2Hz), 8.67(d 1H J=4.4Hz), 9.14(s 1H), 12.15(s 1H), 13.76(s 1H)

Embodiment 1-7:

4-[5-(2-Hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl] Oxy}butyrate hydrochloride

4-{[5-(2-Hydroxy-2-pyridin-3-ylethenyl)-7-methoxy-2,3-dihydroimidazo[1,2-c in 4N HCl was stirred at room temperature ]quinazolin-8-yl]oxyl}butyric acid (Example 1-6) 4.0mg (9.5μmol) in 1,4-dioxane 2.0mL the mixture was stirred for 2 hours, the reaction mixture was diluted with ether, The precipitate was collected to obtain 4.00 mg of the title compound as a yellow solid, with a yield of 92.0%.

Melting point: 249-251°C

Mass spectrum: 423

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: A

H-NMR (500MHz, DMSO-d ₆ ) δ: 2.06 (quint 2H J = 7.3Hz), 2.46 (t 2HJ = 7.3Hz), 4.01 (s 3H), 4.24 (t 2H J = 9.0Hz), 4.29(t 2H J=7.3Hz), 4.45(t 2H J=9.0Hz), 6.18(s 1H), 7.36(d 1H J=9.1Hz), 7.70(dd 1HJ=7.9Hz, 5.0Hz), 8.14( d 1H J=9.1Hz), 8.56(br d 1H J=7.9Hz), 8.82(br d 1H J=5.0Hz), 9.34(s 1H), 12.34(s 1H), 14.57(s 1H)

Embodiment 1-8:

2-[7-methoxy-8-(4-morpholin-4-yl-4-oxobutoxy)-2,3-dihydroimidazo[1,2c]quinazolin-5-yl ]-1-pyridin-3-yl vinyl alcohol

To 4-{[5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazoline-8- Base] oxy}butyric acid (Example 1-6) 20.0mg (0.044mmol), morpholine 19.0mg (0.22mmol) and N, N-diisopropylethylamine 0.038mL (0.22mmol) in N, N - Add PyBOP (1H-1,2,3-benzotriazol-1-yloxy) (tripyrrolidin-1-yl) phosphonium hexafluorophosphate 34.0 mg to a solution in 2.0 mL of dimethylformamide (0.065 mmol), stirred overnight at 80°C. After cooling to room temperature, the reaction mixture was poured into water, and the precipitate was collected and washed with water to obtain 13.0 mg of the title compound as a white solid, with a yield of 60.7%.

Melting point: 234-235°C

Mass spectrum: 492

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: A

H-NMR (500MHz, DMSO-d ₆ ) δ: 2.03(quint 2H J=6.6Hz), 3.46(m 4H), 3.56(m 4H), 3.96(s 3H), 3.99(brd 2H J=8.2Hz) , 4.05(br d 2HJ=8.2Hz), 4.15(t 2H J=6.6Hz), 5.66(s 1H), 6.98(d J=8.8Hz), 7.50(dd 1H J=7.7Hz, 4.7Hz), 7.57 (d 1H J=8.8Hz), 8.29(brd 1HJ=7.7Hz), 8.67(brd 1H J=4.7Hz), 9.14(s 1H), 13.76(s 1H)

In a similar method according to the above-mentioned Examples 1-1 to 1-8, the compounds in Examples 1-9 to 1-210 were synthesized.

Table 1

Example 2-1:

N-(2,3-Dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide

(1) 2-(4,5-Dihydro-IH-imidazol-2-yl)aniline

2-Aminobenzonitrile (9.00 g, 76.2 mmol) was added to ethylenediamine (25.5 ml, 381 mmol) in small portions under stirring at 0°C. After adding phosphorus pentasulfide (200mg, 0.900mmol), the mixture was stirred at 100°C overnight. After cooling to 0°C, the reaction solution was diluted with water. The resulting white precipitate was collected by filtration, washed with water and ether, and dried under reduced pressure to give 2-(4,5-dihydro-1H-imidazol-2-yl)aniline (10.0 g, 81% yield).

(2) 2,3-dihydroimidazo[1,2-c]quinazolin-5-ylamine hydrobromide

To a suspension of 2-(4,5-dihydro-1H-imidazol-2-yl)aniline (5.00 g, 31.0 mmol) in 85% methanol (60 ml) was added cyanogen bromide (3.61 g , 34.1 mmol), and the mixture was stirred overnight at room temperature. After the mixture was concentrated under reduced pressure, the resulting precipitate was collected by filtration. The green solid was washed with water, methanol and ether successively, and dried under reduced pressure to obtain 2,3-dihydroimidazo[1,2-c]quinazolin-5-ylamine hydrobromide (4.94g, 60% yield ).

(3) N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide

To 2,3-dihydroimidazo[1,2-c]quinazolin-5-ylamine hydrobromide (500mg, 1.87mmol) and nicotinic acid (346mg, 2.81mmol) at room temperature in N,N - Add benzotriazol-1-yloxy-tripyrrolidine-phosphonium hexafluorophosphate (1.46 g, 2.81 mmol) and N,N-diisopropyl to a suspension in dimethylformamide (25 ml) Ethylamine (1.30ml, 7.49mmol). The mixture was heated at 80 °C for 4 hours, after cooling to room temperature, the mixture was quenched with aqueous saturated NaHCO ₃ solution. The resulting precipitate was collected by filtration, washed with water and ether, and dried under reduced pressure to obtain N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (450mg, 83% yield ).

Melting point: 238-239°C (decomposition)

Mass spectrum: 292

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: A

¹ H-NMR (300Hz, DMSO-d ₆ ): δ4.00-4.11 (2H, m), 4.11-4.21 (2H, m), 7.29 (1H, ddd, J=3.0, 5.3, 7.9Hz), 7.52 (1H,dd,J=4.9,7.9Hz), 7.57-7.66(2H,m), 7.89(1H,d,J=7.9Hz), 8.42-8.48(1H,m), 8.73(1H,dd,J = 1.9, 4.9 Hz), 9.32 (1H, d, J = 1.1 Hz), 12.36 (1H, s).

Example 2-2:

N-(2,3-Dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide hydrochloride

To a suspension of N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (150mg, 0.515mmol) in THF (4ml) was added hydrochloric acid at 0°C 4N solution in 1,4-dioxane (2ml, 8mmol). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained residue was triturated with diethyl ether, and the obtained precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide Hydrochloride (192 mg, quantitative).

Melting point: 289°C (decomposition)

Mass spectrum: 292

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: A

¹ H-NMR (300MHz, DMSO-d ₆ ): δ4.18-4.30 (2H, m), 4.54-4.65 (2H, m), 7.56-7.65 (1H, m), 7.88 (1H, dd, J= 4.9, 7.9Hz), 7.97-8.10 (2H, m), 8.64 (1H, d, J = 7.9Hz), 8.80 (1H, d, J = 7.9Hz), 8.95 (1H, dd, J = 1.5, 5.3 Hz), 9.43 (1H, d, J = 1.1 Hz), 12.7-13.3 (1H, br).

Embodiment 2-3:

6-(Acetamido)-N-[8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide

(1) 4-(morpholin-4-yl)-2-nitrobenzonitrile

A mixture of 4.20 g (21.75 mmol) of 2,4-dinitrobenzonitrile and 5.7 mL (66.0 mmol) of morpholine in 20 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The reaction mixture was poured into water, and the precipitate was collected and washed with water to obtain 4.20 g of the title compound as an orange solid, with a yield of 74.5%.

(2) 2-Amino-4-(morpholin-4-yl)benzonitrile

Add 4.20 g (16.09 g) of 4-(morpholin-4-yl)-2-nitrobenzonitrile to an ice-cooled mixture of 12.8 g (56.7 mmol) of tin(II) chloride dihydrate in 40 mL of concentrated hydrochloric acid mmol), stirred at room temperature for 2 hours. The reaction mixture was poured into dilute NaOH solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over _MgSO4 , and the solvent was evaporated. The crude product was washed with ether to obtain 3.13 g of the title compound as an off-white solid, with a yield of 95.0%.

(3) [2-(4,5-dihydro-1H-imidazol-2-yl)-5-(morpholin-4-yl)phenyl]amine

Add 4.00 mg (0.018 mmol) of phosphorus pentasulfide to a solution of 3.65 g (18.0 mmol) of 2-amino-4-(morpholin-4-yl)benzonitrile in 20 mL of ethylenediamine, and stir at 140° C. for 16 hours . After cooling to room temperature, the solvent was evaporated. The residue was washed with water and diethyl ether to obtain 3.70 g of the title compound as an off-white solid with a yield of 83.5%.

(4) 8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine hydrobromide

To the suspension of [2-(4,5-dihydro-1H-imidazol-2-yl)-5-(morpholin-4-yl)phenyl]amine 3.60g (14.6mmol) in 2-propanol 20mL 2.32 g (21.9 mmol) of cyanogen bromide was added in batches to the liquid at 0°C, and stirred at 100°C for 2 hours. After cooling to room temperature, the precipitate was collected and washed with diethyl ether to obtain 1.20 g of the title compound as a yellow solid, yield 77.5%.

(5) 6-(Acetylamino)niacin

A mixture of 5.00 g (36.5 mmol) of 6-aminonicotinic acid and 3.80 mL (40.2 mmol) of acetic anhydride in 30 mL of pyridine was stirred at 140° C. for 24 hours, ethyl acetate was added to the reaction mixture, and acidified to pH 2 with dilute hydrochloric acid solution. The organic layer was washed with water and brine, dried over _MgSO4 , filtered and the solvent was evaporated. The residue was washed with diisopropyl ether to obtain the title compound as an off-white solid (1.70 g, yield 26%).

(6) 6-(acetylamino)-N-[8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide

To 8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine hydrobromide 105.7mg (0.30mmol), 6-(acetylamino ) Niacin 81.1mg (0.45mmol) and N, N-diisopropylethylamine 0.26mL (1.50mmol) in the mixture of N, N-dimethylformamide 2mL, add PyBOP ((1H-1,2 , 3-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate) 234.2 mg (0.45 mmol), stirred at 90°C for 16 hours. After cooling to room temperature, saturated NaHCO ₃ solution was added. The precipitate was collected and washed with water, methanol and diethyl ether to obtain 41.1 mg of the title compound as a yellow solid, with a yield of 31.6%.

Melting point: 228°C

Mass spectrum: 434

In vitro PI3K-β inhibitory activity: C

In vitro PI3K-γ inhibitory activity: A

H-NMR (500MHz, DMSO-d ₆ )δ: 3.22-3.30(m 4H), 3.74(s 3H), 3.86(m2H), 3.97(m 2H), 6.77(br s 1H), 7.60(m 1H) , 8.07(m 1H), 8.32(m1H), 8.95(br s 1H), 10.60(s 1H)

Embodiment 2-4:

6-(Acetamido)-N-[8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide hydrochloride

To 6-(acetylamino)-N-[8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]-quinazolin-5-yl]nicotinamide (implementation Example 2-3) To a mixture of 20.0 mg (0.046 mmol) in 1.5 mL of 1,4-dioxane was added 4N hydrochloric acid in 0.5 mL of 1,4-dioxane, and stirred at room temperature for 40 minutes. The precipitate was collected and washed with ether to give the title compound as a yellow solid, 17.0 mg, 78%.

Melting point: 237°C

Mass spectrum: 434

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: A

H-NMR (500MHz, DMSO-d ₆ ) δ: 3.41-3.76(m 7H), 3.86(m 2H), 4.10(m2H), 7.20(m 1H), 7.39(m 1H), 8.19(m 1H), 8.45(m 1H), 9.09(br s1H), 10.86(s 1H)

Embodiment 2-5:

N-(8-Hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide

N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Example 2-22) 3.50g (10.9mmol) and sulfide A suspension of sodium 4.25 g (54.5 mmol) in 1-methyl-2-pyrrolidone 10 mL was heated to 160° C. for 4 h (LC-MS showed complete consumption of starting material). The mixture was cooled to room temperature and volatile by-products were evaporated. The mixture was partitioned between chloroform and 0.5N NaOH solution, the aqueous layer was neutralized, and the formed precipitate was collected to obtain 2.34 g of the title compound as an off-white solid, with a yield of 69.9%.

Melting point: 289°C

Mass spectrum: 308

In vitro PI3K-β inhibitory activity: C

In vitro PI3K-γ inhibitory activity: B

H-NMR (500MHz, DMSO-d ₆ ) δ: 4.01(m 2H), 4.15(m 2H), 6.75(dd 1H J=8Hz, 2Hz), 6.91(s 1H), 7.52(dd 1H J=8Hz, 5Hz), 7.75(d 1H J=8Hz), 8.44(d1H J=8Hz), 8.73(dd 1H J=5Hz, 2Hz), 9.31(s 1H), 10.61(br s 1H), 12.24(br s 1H)

Embodiment 2-6:

N-{8-[2-(1-pyrrolyl)ethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide

In a sealed tube, 70.0 mg (0.23 mmol) of N-(8-hydroxy-2,3-dihydroimidazo[1,2-cJ quinazolin-5-yl]nicotinamide (Example 2-1), A suspension of 47.6mg (0.27mmol) of N-(2-bromoethyl)pyrrole and 126mg (0.91mmol) of potassium carbonate in 5mL of N,N-dimethylformamide was heated to 120°C for 3 hours. The reaction mixture was concentrated, Partitioned between dichloromethane and water, the organic layer was washed with 0.1N NaOH solution and brine, dried over _Na2SO4 , and the solvent _was evaporated to give the title compound as an off-white solid, 49.0 mg, yield 54%.

Melting point: 209°C

Mass spectrum: 401

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: B

H-NMR (500MHz, DMSO-d ₆ ) δ: 4.00(m 2H), 4.12(m 2H), 4.30(s 4H), 6.00(m 2H), 6.84(m 2H), 6.85(dd 1H J=6Hz , 2Hz), 7.27(d 1H J=2Hz), 7.52(dd 1H J=6Hz), 7.76(d 1H J=8Hz), 8.44(dd 1H J=8Hz, 2Hz), 8.72(dd 1H J=5Hz, 2Hz), 9.31(s 1H), 12.32(s 1H).

The compounds in Examples 2-7 to 2-368 were synthesized in a similar manner according to the above-mentioned Examples 2-1 to 2-6.

Table 2

Example 3-1:

(Z)-2-imidazo[1,2-clquinazolin-5-yl-1-(2-thiophene)vinyl alcohol

(1) 2-(1H-imidazol-2-yl)aniline

2-(4,5-Dihydro-1H-imidazol-2-yl)aniline hydrobromide (50.0mg, 0.207mmol) and manganese dioxide (170mg, 1.96mmol) were dissolved in N,N'-dimethyl The mixture in propylurea (2.0 mL) was heated at 150°C (bath temperature). After 1 hour, the reaction mixture was cooled to room temperature, poured into a solution of bromehydrochloride (0.5 g) in water (50 mL), and the resulting mixture was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The crude residue was triturated with isopropyl ether, the precipitate was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (silica gel, ethyl acetate as eluent) to obtain 2-(1H-imidazole-2- yl)aniline (20 mg, 61% yield).

(2) Ethyl 3-oxo-3-(2-thienyl)propionate

To a suspension of 2-thiophenecarboxylic acid (6.48g, 50.57mmol) in tetrahydrofuran (100ml) was added portionwise at 5°C 1,1'-carbonylbiimidazole (8.61g, 53.09mmol), and the mixture was warmed to Stirring was continued for 1 hour at room temperature. The reaction mixture was added to the suspension hydrate of magnesium chloride (4.86g, 51.07mmol) and 3-ethoxy-3-oxopropionate (12.91g, 75.85mmol) in tetrahydrofuran (50ml), stirred at 50°C for 2 After stirring for 2 hours and overnight at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over _MgSO4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, 15/85) to obtain ethyl 3-oxo-3-(2-thienyl)propionate- (7.83 g, 78% yield).

(3) (Z)-2-imidazo[1,2-c]quinazolin-5-yl-1-(2-thienyl)vinyl alcohol

2-(1H-imidazol-2-yl)aniline (60.0mg, 0.38mmol), ethyl 3-oxo-3-(2thienyl)propionate (74.7mg, 0.38mmol) and p-toluenesulfonic acid mono A mixture of the hydrate (36.1 mg, 0.19 mmol) in toluene (30 mL) was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was poured into saturated NaHCO ₃ solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, 2/3-1/1) to obtain (Z)-2-imidazo[1,2-c]quinazolin-5-yl-1- (2-Thienyl)vinyl alcohol (37.0 mg, 33% yield).

Melting point: 128°C

Mass spectrum: 294

In vitro PI3K-β inhibitory activity:

In vitro PI3K-γ inhibitory activity: D

¹ H-NMR (300MHz, CDCl3): δ

6.11(1H, s), 7.16(1H, dd, J=3.8, 4.9Hz), 7.34-7.41(2H, m), 7.53-7.60(3H, m), 7.64(1H, d, J=1.7Hz) , 7.73 (1H, dd, J=1.1, 3.8 Hz), 8.34 (1H, dd, J=0.9, 7.8 Hz), 14.70 (1H, bs).

Example 3-2

(Z)-2-imidazo[1,2-c]quinazolin-5-yl-1-(2-thienyl)vinyl alcohol hydrochloride

To a solution of (Z)-2-imidazo[1,2-c]quinazolin-5-yl-1-(2-thienyl)vinyl alcohol (0.06g, 0.07mmol) in chloroform (1.0ml) 4N HCl1,4-dioxane solution (0.5ml) was added to it. The mixture was diluted with ether, and the resulting precipitate was collected by filtration, washed with ether, and dried under reduced pressure to obtain (Z)-2-imidazo[1,2-c]quinazolin-5-yl-1-(2-thienyl) Vinyl alcohol hydrochloride (0.07 g, quantitative) was a yellow solid.

Melting point: 263°C (decomposition)

Mass spectrum: 294

In vitro PI3K-β inhibitory activity:

In vitro PI3K-γ inhibitory activity: D

¹ H-NMR (300MHz, DMSO-d ₆ ): δ6.79 (1H, s), 7.28 (1H, dd, J=3.8, 4.9Hz), 7.45 (1H, t, J=7.0Hz), 7.66- 7.77 (2H, m), 7.82 (1H, d, 1.7), 7.91 (1H, dd, J=1.1, 5.0Hz), 8.17 (1H, dd, J=1.1, 3.8Hz), 8.30 (1H, dd, J = 1.0, 8.0 Hz), 8.62 (1H, d, J 1.7 Hz), 14.36 (1H, br).

Example 4-1:

N-imidazo[1,2-c]quinazolin-5-ylnicotinamide

(1) Imidazo[1,2-c]quinazolin-5-amine

To a solution of 2-(1H-imidazol-2-yl)aniline (0.06g.0.38mmol) in methanol (3ml) was added cyanogen bromide (0.05g, 0.45mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting precipitate was collected by filtration, washed with acetone, and dried under reduced pressure to obtain imidazo[1,2-c]quinazolin-5-amine hydrobromide (0.06g, 61% yield) white solid.

(2) N-imidazo[1,2-c]quinazolin-5-ylnicotinamide

To a mixture of imidazo[1,2-c]quinazolin-5-amine hydrobromide (93mg, 0.35mmol) and nicotinic acid (124mg, 1.01mmol) and DMF (2.5ml) was added benzotriazole -1-yloxy-tripyrrolidinyl-phosphonium hexafluorophosphate (525mg, 1.01mmol), then N,N-diisopropylethylamine (0.264ml, 1.51mmol) was added, and the mixture was stirred at 80°C for 6 Hour. After cooling to room temperature, the reaction mixture was poured into aqueous saturated NaHCO ₃ solution. The resulting precipitate was collected by filtration, washed with acetone, and dried under reduced pressure to give N-imidazo[1,2-c]quinazolin-5-ylnicotinamide (40 mg, 39% yield) as a white solid.

Melting point: 223-224°C (decomposition)

Mass spectrum: 290

In vitro PI3K-β inhibitory activity:

In vitro PI3K-γ inhibitory activity: C

¹ H-NMR (300MHz, DMSO-d ₆ ): δ7.53-7.62 (3H, m), 7.70 (1H, t, J = 7.34Hz), 8.00 (1H, d, J = 8.10Hz), 8.30 ( 1H, d, J = 7.91Hz), 8.44 (1H, s), 8.63 (1H, d, J = 7.72Hz), 8.81 (1H, dd, J = 1.5, 4.7Hz), 9.49 (1H, s), 13.49 (1H,br).

Example 4-2

N-imidazo[1,2-c]quinazolin-5-ylnicotinamide hydrochloride

To a solution of N-imidazo[1,2-c]quinazolin-5-ylnicotinamide (40mg, 0.14mmol) in methanol (20ml) was added 4N hydrochloric acid in 1,4-dioxane (0.5 ml), the mixture was concentrated under reduced pressure. The resulting solid was collected by filtration, washed with THF, and dried under reduced pressure to give N-imidazo[1,2-c]quinazolin-5-ylnicotinamide hydrochloride (40 mg, 89% yield) as a white solid.

Melting point: 228°C (decomposition)

Mass spectrum: 290

In vitro PI3K-β inhibitory activity:

In vitro PI3K-γ inhibitory activity: C

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ7.60 (2H, br), 7.65 (1H, t, J=7.5Hz), 7.82 (1H, dd, J=7.3, 8.1Hz), 7.92 ( 1H, s), 8.02 (1H, dd, J = 5.5, 7.9Hz), 8.54 (1H, d, J = 8.3Hz), 8.73 (1H, s), 9.02 (1H, dd, J = 1.3, 5.3Hz ), 9.07 (1H, d, J=7.53Hz), 9.67 (1H, s).

references

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Claims (26)

1. the fused pyrrole pyrimidine derivatives of formula (I), their change and stereoisomeric forms in any ratio and their salt:

Wherein

X represents CR ⁵R ⁶Or NH;

Y ¹Expression CR ³Or N;

Between chemical bond represent singly-bound or two key,

Its prerequisite is,

When During the two key of expression, Y ²And Y ³Represent CR respectively ⁴Or N and

When

During the expression singly-bound, Y ²And Y ³Represent CR respectively ³R ⁴Or NR ⁴

Z ¹, Z ², Z ³And Z ⁴Represent CH, CR respectively ²Or N;

R ¹The optional individual R that is selected from of 1-3 that has of expression ¹¹Substituent aryl,

The optional individual R that is selected from of 1-3 that has ¹¹Substituent C _3-8Cycloalkyl,

Optional by aryl, heteroaryl, C _1-6The C that alkoxy aryl, aryloxy, heteroaryloxy or one or more halogen replace _1-6Alkyl,

Optional by carboxyl, aryl, heteroaryl, C _1-6The C that alkoxy aryl, aryloxy, heteroaryloxy or one or more halogen replace _1-6Alkoxyl group, or

3-15 unit list-or bicyclic heterocycle, it is saturated or undersaturated, the optional individual R that is selected from of 1-3 that has ¹¹Substituting group and contain 1-3 the heteroatoms that is selected from N, O and S,

Wherein

R ¹¹Expression halogen, nitro, hydroxyl, cyano group, carboxyl, amino, N-(C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(C _1-6Acyl group) amino, N-(formyl radical)-N-(C _1-6Alkyl) amino, N-(C _1-6Alkyl sulphonyl) amino, N-(carboxyl C _1-6Alkyl)-N-(C _1-6Alkyl) amino, N-(C _1-6Alkoxy carbonyl) amino, N-[N, N-two (C _1-6Alkyl) aminomethylene] amino, N-[N, N-two (C _1-6Alkyl) amino (C _1-6Alkyl) methylene radical] amino, N-[N, N-two (C _1-6Alkyl) amino C _2-6Thiazolinyl] amino, aminocarboxyl, N-(C _1-6Alkyl) aminocarboxyl, N, N-two (C _1-6Alkyl) aminocarboxyl, C _3-8Cycloalkyl, C _1-6Alkylthio, C _1-6Alkyl sulphonyl, amino-sulfonyl, C _1-6Alkoxy carbonyl,

The N-arylamino, the optional individual R that is selected from of 1-3 that has of wherein said aryl moiety ¹⁰¹Substituting group, N-(aryl C _1-6Alkyl) amino, the optional individual R that is selected from of 1-3 that has of wherein said aryl moiety ¹⁰¹Substituting group, aryl C _1-6Alkoxy carbonyl, the optional individual R that is selected from of 1-3 that has of wherein said aryl moiety ¹⁰¹Substituting group,

Optional coverlet-, two-or three-halogen, amino, N-(C _1-6Alkyl) amino or N, N-two (C _1-6Alkyl) the amino C that replaces _1-6Alkyl,

Optional coverlet-, two-or three-halogen, amino, N-(C _1-6Alkyl) C of sulphonamide or N-(aryl) sulfonamide substitutions _1-6Alkoxyl group, or

Saturated or the unsaturated ring of 5-7 unit contains 1-3 heteroatoms and the optional individual R that is selected from of 1-3 that has that is selected from O, S and N ¹⁰¹Substituting group,

Wherein

R ¹⁰¹Expression halogen, carboxyl, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, aminocarboxyl, N-(C _1-6Alkyl) aminocarboxyl, N, N-two (C _1-6Alkyl) aminocarboxyl, pyridyl,

Optional by cyano group or single-, two-or the C that replaces of three-halogen _1-6Alkyl, or

Optional by cyano group, carboxyl, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, aminocarboxyl, N-(C _1-6Alkyl) aminocarboxyl, N, N-two (C _1-6Alkyl) aminocarboxyl or single-, two-or the C that replaces of three-halogen _1-6Alkoxyl group;

R ²Expression hydroxyl, halogen, nitro, cyano group, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl)-N-(C _1-6Alkyl) amino, C _1-6Acyloxy, amino C _1-6Acyloxy, C _2-6Thiazolinyl, aryl,

Saturated or the unsaturated heterocycle of 5-7 unit, it contains 1-3 heteroatoms that is selected from O, S and N, and is optional by hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, oxo, amino, amino C _1-6Alkyl, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(C _1-6Acyl group) amino, N-(C _1-6Alkyl) carbonylamino, phenyl, phenyl C _1-6Alkyl, carboxyl, C _1-6Alkoxy carbonyl, aminocarboxyl, N-(C _1-6Alkyl) aminocarboxyl or N, N-two (C _1-6Amino replacement alkyl),

-C(O)-R ²⁰

Wherein

R ²⁰Expression C _1-6Alkyl, C _1-6Alkoxyl group, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(C _1-6Acyl group) cyano group, or the saturated or unsaturated heterocycle of 5-7 unit, it contains 1-3 heteroatoms that is selected from O, S and N, and optional by C _1-6Alkyl, C _1-6Alkoxyl group, oxo, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(C _1-6Acyl group) amino, phenyl or benzyl replace,

By R ²¹The optional C that replaces _1-6Alkyl or

By R ²¹The optional C that replaces _1-6Alkoxyl group,

Wherein

R ²¹Expression cyano group, list-, two-or three-halogen, hydroxyl, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl) amino, N-(halogenophenyl C _1-6Alkyl) amino, amino C _2-6Thiazolinyl, C _1-6Alkoxyl group, hydroxyl C _1-6Alkoxyl group ,-C (O)-R ²⁰¹,-NHC (O)-R ²⁰¹, C _3-8Cycloalkyl, pseudoindoyl, phthaloyl imino, 2-oxo-1,3-oxazolidinyl, aryl, or 5 or 6 yuan of saturated or unsaturated heterocycles, it contains 1-4 heteroatoms that is selected from O, S and N, and is optional by hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Alkoxy carbonyl, hydroxyl C _1-6Alkoxyl group, oxo, amino, amino C _1-6Alkyl, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(C _1-6Acyl group) cyano group or benzyl replace,

Wherein

R ²⁰¹Expression hydroxyl, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(halogenophenyl C _1-6Alkyl) amino, C _1-6Alkyl, amino C _1-6Alkyl, amino C _2-6Thiazolinyl, C _1-6Alkoxyl group, or 5 or 6 yuan of saturated or unsaturated heterocycles, it contains 1-4 heteroatoms that is selected from O, S and N, and is optional by hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Alkoxy carbonyl, hydroxyl C _1-6Alkoxyl group, oxo, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(C _1-6Acyl group) cyano group or benzyl replace,

R ³Expression H, halogen, aminocarboxyl or by aryl C _1-6Alkoxyl group or single-, two-or the optional C that replaces of three-halogen _1-6Alkyl;

R ⁴Expression H or C _1-6Alkyl;

R ⁵Expression H or C _1-6Alkyl; With

R ⁶Expression halogen, H or C _1-6Alkyl.

2. the formula of claim 1 (I) fused pyrrole pyrimidine derivatives, its change or stereoisomeric forms in any ratio or its salt;

Wherein

X represents CR ⁵R ⁶Or NH;

Y ¹Expression CR ³Or N;

Between chemical bond represent singly-bound or two key,

Its prerequisite is,

When

During the two key of expression, Y ²And Y ³Represent CR respectively ⁴Or N and

When

During the expression singly-bound, Y ²And Y ³Represent CR respectively ³R ⁴Or NR ⁴

Z ¹, Z ², Z ³And Z ⁴Represent CH, CR respectively ²Or N;

R ¹Expression

Optional coverlet-, two-or the C that replaces of three-halogen, phenyl, p-methoxy-phenyl, phenoxy group or thienyl _1-6Alkyl,

Optional coverlet-, two-or the C that replaces of three-halogen, phenyl, p-methoxy-phenyl, phenoxy group or thienyl _1-6Alkoxyl group,

Or

One of following carbocyclic ring and heterocycle, it is selected from cyclopropyl, cyclohexyl, piperidyl, piperazinyl, pyrryl, pyrazolyl, furyl, thienyl, thiazolyl, isothiazolyl oxazolyl isoxazolyl, imidazolyl, different imidazolyl, pyrazolyl, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, 1,2, the 5-triazolyl, 1,3, the 4-triazolyl, phenyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, the 1-benzothienyl, benzothiazolyl, benzimidazolyl-, 3H-imidazo [4,5-b] pyridyl, the benzotriazole base, indyl, indazolyl, imidazo [1,2-b] pyridyl, quinolyl and 1, the 8-naphthyridinyl

Wherein

Described carbocyclic ring and heterocycle are optional to be replaced by 1-3 substituting group, and substituting group is selected from hydroxyl, halogen, nitro, cyano group, carboxyl, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(C _1-6Acyl group) amino, N-(C _1-6Alkoxy carbonyl) amino, N-(formyl radical)-N-(C _1-6Alkyl) amino, N-[N, N-two (C _1-6Alkyl) aminomethylene] amino, N-[N, N-two (C _1-6Alkyl) amino (C _1-6Alkylidene group) methylene radical] amino, N-[N, N-two (C _1-6Alkyl) amino C _2-6Thiazolinyl] amino, C _1-6Alkylthio, C _1-6Alkyl sulphonyl, amino-sulfonyl, C _1-6Alkoxyl group, C _1-6Alkoxy carbonyl, pyrryl, imidazolyl, pyrazinyl, pyrrolidyl, pyridyl, phenyl C _1-6Alkoxy carbonyl,

The optional thiazolyl that replaces of pyridyl,

By C _1-6Alkyl or C _1-6The optional piperazinyl that replaces of alkoxyl group and

Coverlet-, two-or the optional C that replaces of three-halogen _1-6Alkyl;

R ²Expression hydroxyl, halogen, nitro, cyano group, carboxyl, amino, N-(C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl)-N-(C _1-6Alkyl) amino, C _2-6Thiazolinyl, C _1-6Alkoxy carbonyl, aminocarboxyl, C _1-6Acyloxy, amino C _1-6Acyloxy, furyl, morpholino, phenyl, piperidino-(1-position only), aryl,

By C _1-6The optional pyrrolidyl that replaces of amido,

By hydroxyl, C _1-6Alkyl, carboxyl, aminocarboxyl, N-(C _1-6Alkyl) aminocarboxyl or N, N-two (C _1-6Alkyl) the optional piperidino-(1-position only) that replaces of aminocarboxyl,

By C _1-6The optional piperazinyl that replaces of alkyl,

By cyano group, list-, two-or three-halogen, hydroxyl, amino, N-(C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, C _3-6Cycloalkyl, tetrazyl, THP trtrahydropyranyl, morpholino, phthaloyl imino, 2-oxo-1,3-oxazolidinyl, the optional C that replaces of phenyl _1-6Alkyl,

-C(O)-R ²⁰¹、

By C _1-6The optional pyrrolidyl that replaces of amido,

By hydroxyl, C _1-6Alkyl, carboxyl, aminocarboxyl, N-(C _1-6Alkyl) aminocarboxyl or N, N-two (C _1-6Alkyl) the optional piperidino-(1-position only) that replaces of aminocarboxyl or

By C _1-6The optional piperazinyl that replaces of alkyl,

Wherein

R ²⁰¹Expression hydroxyl, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, amino, the C of N-(halogeno-benzyl) _1-6Alkyl, C _1-6Alkoxyl group, tetrazyl, THP trtrahydropyranyl, morpholino,

By C _1-6The optional pyrrolidyl that replaces of amido,

By hydroxyl, C _1-6Alkyl, carboxyl, aminocarboxyl, N-(C _1-6Alkyl) aminocarboxyl or N, N-two (C _1-6Alkyl) the optional piperidino-(1-position only) that replaces of aminocarboxyl,

Or

By C _1-6The optional piperazinyl that replaces of alkyl,

By cyano group, list-, two-or three-halogen, hydroxyl, C _1-6Alkoxyl group, hydroxyl C _1-6Alkoxyl group, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, pyrryl, tetrazyl, THP trtrahydropyranyl, morpholino, phthaloyl imino, 2-oxo-1,3-oxazolidinyl, phenyl ,-C (O)-R ²⁰¹The optional C that replaces _1-6Alkyl,

By C _1-6The optional pyrrolidyl that replaces of amido,

By hydroxyl, C _1-6Alkyl, carboxyl, aminocarboxyl, N-(C _1-6Alkyl) aminocarboxyl or N, N-two (C _1-6Alkyl) the optional piperidino-(1-position only) that replaces of aminocarboxyl or

By C _1-6The optional piperazinyl that replaces of alkyl,

Wherein

R ²⁰¹Expression hydroxyl, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, amino, the C of N-(halogeno-benzyl) _1-6Alkyl, C _1-6Alkoxyl group, amino C _2-6Thiazolinyl, tetrazyl, THP trtrahydropyranyl, morpholino, by C _1-6The optional pyrrolidyl that replaces of amido, by hydroxyl, C _1-6Alkyl, carboxyl, aminocarboxyl, N-(C _1-6Alkyl) aminocarboxyl or N, N-two (C _1-6Alkyl) the optional piperidino-(1-position only) that replaces of aminocarboxyl,

Or by C _1-6The optional piperazinyl that replaces of alkyl,

R ³Expression H, halogen, by aminocarboxyl, aryl C _1-6Alkoxyl group or single-, two-or the optional C that replaces of three-halogen _1-6Alkyl;

R ⁴Expression H or C _1-6Alkyl;

R ⁵Expression H or C _1-6Alkyl; With

R ⁶Expression halogen, H or C _1-6Alkyl.

3. the fused pyrrole pyrimidine derivatives of the formula of claim 1 (I), its change or stereoisomeric forms in any ratio or its salt:

Wherein

X represents CR ⁵R ⁶Or NH;

Y ¹Expression N;

Y ²And Y ³Expression CR ³R ⁴

Chemical bond The expression singly-bound,

Z ⁴Expression CH;

Z ¹, Z ²And Z ³Represent N, CH or CR respectively ²

R ¹Expression

Optional coverlet-, two-or the C that replaces of three-halogen, phenyl, p-methoxy-phenyl, phenoxy group or thienyl _1-6Alkyl,

Optional by phenyl, phenoxy group, thienyl or single-, two-or the C of three-halogen, replacement _1-6Alkoxyl group,

Or

One of following carbocyclic ring and heterocycle, it is selected from cyclopropyl, cyclopentyl, cyclohexyl, piperidyl, piperazinyl, pyrryl, pyrazolyl, furyl, thienyl, thiazolyl, isothiazolyl oxazolyl isoxazolyl, imidazolyl, different imidazolyl, pyrazolyl, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, 1,2, the 5-triazolyl, 1,3, the 4-triazolyl, phenyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, the 1-benzothienyl, benzothiazolyl, benzimidazolyl-, 3H-imidazo [4,5-b] pyridyl, the benzotriazole base, indyl, indazolyl, imidazo [1,2-b] pyridyl, quinolyl and 1, the 8-naphthyridinyl

Wherein

Described carbocyclic ring and heterocycle are optional to be replaced by 1-3 substituting group, and substituting group is selected from hydroxyl, halogen, nitro, cyano group, carboxyl, amino, N-(C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(C _1-6Acyl group) amino, N-(C _1-6Alkoxy carbonyl) amino, N-(formyl radical)-N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino (C _2-6Thiazolinyl) amino, N-(C _1-6Alkyl) sulfuryl amino, N-[N, N-two (C _1-6Alkyl) aminomethylene] amino, C _1-6Alkylthio, C _1-6Alkyl sulphonyl, amino-sulfonyl, C _1-6Alkoxyl group, C _1-6Alkoxy carbonyl, pyrryl, imidazolyl, pyrazinyl, pyrrolidyl, pyridyl, phenyl C _1-6Alkoxy carbonyl,

The optional thiazolyl that replaces of pyridyl, by C _1-6Alkyl or C _1-6The optional piperazinyl that replaces of alkoxyl group and

Coverlet-, two-or the optional C that replaces of three-halogen _1-6Alkyl;

R ²Expression hydroxyl, halogen, nitro, cyano group, carboxyl, amino, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl)-N-(C _1-6Alkyl) amino, (C _2-6) thiazolinyl, C _1-6Alkoxy carbonyl, aminocarboxyl, furyl, piperidino-(1-position only), morpholino, phenyl,

By N-(C _1-6Acyl group) amino optional pyrrolidyl or the N-(C that replaces _1-6Alkyl) aminocarboxyl

By the optional piperidino-(1-position only) that replaces of hydroxyl,

By C _1-6Alkyl, phenyl C _1-6Alkyl, C _1-6The optional piperazinyl that replaces of alkoxy carbonyl or aminocarboxyl;

By amino, cyano group, C _1-6Alkoxy carbonyl, morpholino or single, the optional C that replaces of two or three halogens _1-6Alkyl,

Or

By hydroxyl, cyano group, carboxyl, C _1-6Alkoxyl group, C _1-6Acyl group, C _1-6Alkoxy carbonyl, amino, N-(C _1-6Alkyl) amino, N-(C _1-6Alkyl) aminocarboxyl, N, N-two (C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) aminocarboxyl, aminocarboxyl, amino C _1-6Alkyl-carbonyl, N-(halogeno-benzyl) aminocarboxyl, hydroxyl C _1-6Alkoxyl group, C _3-6Cycloalkyl, morpholino, morpholino carbonyl, pyrrolidyl, pyrryl, piperidino-(1-position only), the optional C that replaces of phthaloyl imino _1-6Alkoxyl group,

Or

By the optional piperazinyl that replaces of benzyl;

R ³Expression H;

R ⁴Expression H;

R ⁵Expression H; With

R ⁶Expression H.

4. the formula of claim 1 (I) fused pyrrole pyrimidine derivatives, its change or stereoisomeric forms in any ratio or its salt:

Wherein

X represents CR ⁵R ⁶Or NH;

Y ¹Expression N;

Y ²And Y ³Expression CR ³R ⁴

Between chemical bond represent singly-bound,

Z ⁴Expression CH;

Z ¹, Z ²And Z ³Represent N, CH or CR respectively ²

R ¹Representative ring propyl group, cyclopentyl, cyclohexyl, 2-furyl, 3-furyl, imidazolyl, pyrimidyl, pyridazinyl, piperazinyl, 1,2,3-thiadiazolyl group, 1,3-benzothiazolyl, quinolyl, 3H-imidazo [4,5-b] pyridyl,

By C _1-6The optional 1H-pyrroles-2-base that replaces of alkyl,

By C _1-6The optional 1H-pyrroles-3-base that replaces of alkyl, by 1 or 2 C _1-6The optional pyrazolyl that replaces of alkyl, by 1 or 2 C _1-6The optional replacement of alkyl De isoxazolyl,

By chlorine, nitro, cyano group or C _1-6The optional 2-thienyl that replaces of alkyl,

By chlorine, nitro, cyano group or C _1-6The optional 3-thienyl that replaces of alkyl,

By C _1-6The optional piperidyl that replaces of alkoxy carbonyl or benzyloxycarbonyl,

By the optional phenyl that replaces of 1-3 substituting group, substituting group is selected from: fluorine, chlorine, hydroxyl, nitro, cyano group, carboxyl, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Alkoxy carbonyl, amino, N-(C _1-6Alkyl) amino, N-(C _1-6Acyl group) amino, N-(C _1-6Alkoxy carbonyl) amino, N, N-two (C _1-6Alkyl) amino, N-(formyl radical)-N-C _1-6Alkylamino, C _1-6Alkylthio, C _1-6Alkyl sulphonyl, sulfamyl, pyrryl, imidazolyl, pyrazolyl and by C _1-6The optional piperazinyl that replaces of alkyl,

By the optional pyridyl that replaces of 1 or 2 substituting group, substituting group is selected from: chlorine, hydroxyl, carboxyl, C _1-6Alkoxyl group, C _1-6Alkylthio, amino, N-(C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(C _1-6Acyl group) amino, N-(C _1-6Alkyl) sulfuryl amino, N-[N, N-two (C _1-6Alkyl) aminomethylene] amino and by the optional C that replaces of three halogens _1-6Alkyl,

By C _1-6The optional piperazinyl that replaces of alkyl,

Be selected from C by 1 or 2 _1-6Alkyl, pyridyl and N-(C _1-6Alkoxy carbonyl) the optional 1,3-thiazoles base that replaces of An Ji substituting group,

By C _1-6The optional indyl that replaces of alkyl,

By C _1-6Alkyl or three halo C _1-6The optional benzimidazolyl-that replaces of alkyl,

By C _1-61,2 of the optional replacement of alkyl, 3-benzotriazole base,

By the optional C that replaces of three halogens _1-61 of the optional replacement of alkyl, the 8-naphthyridinyl,

By the optional C that replaces of three halogens, phenyl, phenoxy group or thienyl _1-6Alkyl,

Or

By the optional C that replaces of phenyl, phenoxy group or thienyl _1-6Alkoxyl group;

R ²Expression fluorine, chlorine, bromine, hydroxyl, nitro, vinyl, cyano group, amino, glycyl oxygen base, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl)-N-(C _1-6Alkyl) amino, 2-furyl, piperidino-(1-position only), morpholino, phenyl,

By the optional pyrrolidyl that replaces of kharophen,

By the optional piperidino-(1-position only) that replaces of hydroxyl,

By methyl, benzyl, C _1-6The optional piperazinyl that replaces of alkoxy carbonyl or aminocarboxyl,

By the optional C that replaces of cyano group, trifluoro, carboxyl, methoxycarbonyl, aminocarboxyl, tert-butoxycarbonyl, THP trtrahydropyranyl or morpholino _1-6Alkyl,

By hydroxyl, cyano group, methoxyl group, methoxycarbonyl, tert-butoxycarbonyl, carboxyl, glycyl, dimethylamino, aminocarboxyl, methylamino carbonyl, dimethylamino carbonyl, sec.-propyl aminocarboxyl, fluoro-benzylamino formyl radical, cyclopropyl, pyrrolidyl, piperidino-(1-position only), THP trtrahydropyranyl, morpholino, morpholino carbonyl, 2-oxo-1,3-oxazolidine-4-base, O-phthalic imide-N-base or hydroxyl C _1-6The optional C that replaces of alkene oxygen base _1-6Alkoxyl group,

R ³Expression H;

R ⁴Expression H;

R ⁵Expression H; With

R ⁶Expression H.

5. the formula of claim 1 (I) fused pyrrole pyrimidine derivatives, its change or stereoisomeric forms in any ratio or its salt:

Wherein

X represents CR ⁵R ⁶Or NH;

Y ¹Expression N;

Y ²And Y ³Expression CR ³R ⁴

Between chemical bond represent singly-bound,

Z ³And Z ⁴Expression CH;

Z ¹And Z ²Represent CH or CR respectively ²

R ¹Representative ring propyl group, cyclopentyl, cyclohexyl, 2-furyl, 3-furyl, imidazolyl, 1H-pyrroles-2-base, 1H-pyrroles-3-base, pyrimidyl, pyridazinyl, piperazinyl, 1,2,3-thiadiazolyl group, 1,3-benzothiazolyl, quinolyl, 3H-imidazo [4,5-b] pyridyl,

By C _1-6The optional pyrryl that replaces of alkyl,

By 1 or 2 C _1-6The optional pyrazolyl that replaces of alkyl, by 1 or 2 C _1-6The optional replacement of alkyl De isoxazolyl,

By chlorine, nitro, cyano group or C _1-6The optional 2-thienyl that replaces of alkyl,

By chlorine, nitro, cyano group or C _1-6The optional 3-thienyl that replaces of alkyl,

By C _1-6The optional piperidyl that replaces of alkoxy carbonyl or benzyloxycarbonyl,

By the optional phenyl that replaces of 1-3 substituting group, substituting group is selected from: fluorine, chlorine, hydroxyl, nitro, cyano group, carboxyl, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Alkoxy carbonyl, amino, N-(C _1-6Alkyl) amino, N-(C _1-6Acyl group) amino, N-(C _1-6Alkoxy carbonyl) amino, N, N-two (C _1-6Alkyl) amino, N-(formyl radical)-N-C _1-6Alkylamino, C _1-6Alkylthio, C _1-6Alkyl sulphonyl, sulfamyl, pyrryl, imidazolyl, pyrazolyl and by C _1-6The optional piperazinyl that replaces of alkyl,

By the optional pyridyl that replaces of 1 or 2 substituting group, substituting group is selected from: chlorine, hydroxyl, carboxyl, C _1-6Alkoxyl group, C _1-6Alkylthio, amino, N-(C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(C _1-6Acyl group) amino, N-(C _1-6Alkyl) sulfuryl amino, N-[N, N-two (C _1-6Alkyl) aminomethylene] amino and by the optional C that replaces of three halogens _1-6Alkyl,

By C _1-6The optional piperazinyl that replaces of alkyl,

Be selected from C by 1 or 2 _1-6Alkyl, pyridyl and N-(C _1-6Alkoxy carbonyl) the optional 1,3-thiazoles base that replaces of An Ji substituting group,

By C _1-6The optional indyl that replaces of alkyl,

By C _1-6Alkyl or three halo C _1-6The optional benzimidazolyl-that replaces of alkyl,

By C _1-61,2 of the optional replacement of alkyl, 3-benzotriazole base,

By the optional C that replaces of three halogens _1-61 of the optional replacement of alkyl, the 8-naphthyridinyl,

By the optional C that replaces of three halogens, phenyl, phenoxy group or thienyl _1-6Alkyl,

Or

By the optional C that replaces of phenyl, phenoxy group or thienyl _1-6Alkoxyl group;

R ²Expression fluorine, chlorine, bromine, hydroxyl, nitro, vinyl, cyano group, amino, glycyl oxygen base, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl)-N-(C _1-6Alkyl) amino, 2-furyl, piperidino-(1-position only), morpholino, phenyl,

By the optional pyrrolidyl that replaces of kharophen,

By the optional piperidino-(1-position only) that replaces of hydroxyl,

By methyl, benzyl, C _1-6The optional piperazinyl that replaces of alkoxy carbonyl or aminocarboxyl,

By the optional C that replaces of cyano group, trifluoro, carboxyl, methoxycarbonyl, aminocarboxyl, tert-butoxycarbonyl, THP trtrahydropyranyl or morpholino _1-6Alkyl,

Or

By hydroxyl, cyano group, methoxyl group, methoxycarbonyl, tert-butoxycarbonyl, carboxyl, glycyl, dimethylamino, aminocarboxyl, methylamino carbonyl, dimethylamino carbonyl, sec.-propyl aminocarboxyl, fluoro-benzylamino formyl radical, cyclopropyl, pyrrolidyl, piperidino-(1-position only), THP trtrahydropyranyl, morpholino, morpholino carbonyl, 2-oxo-1,3-oxazolidine-4-base, O-phthalic imide-N-base or hydroxyl C _1-6The optional C that replaces of alkene oxygen base _1-6Alkoxyl group,

R ³Expression H;

R ⁴Expression H;

R ⁵Expression ^HWith

R ⁶Expression ^H

6. the formula of claim 1 (I) fused pyrrole pyrimidine derivatives, its change or stereoisomeric forms in any ratio or its salt:

Wherein

X represents CR ⁵R ⁶Or NH;

Y ¹Expression N;

Y ²And Y ³Expression CR ³R ⁴

Between chemical bond represent singly-bound,

Z ¹And Z ⁴Expression CH;

Z ²And Z ³Represent CH or CR respectively ²

R ¹Representative ring propyl group, cyclopentyl, cyclohexyl, 2-furyl, 3-furyl, imidazolyl, 1H-pyrroles-2-base, 1H-pyrroles-3-base, pyrimidyl, piperazinyl, pyridazinyl, 1,2,3-thiadiazolyl group, 1,3-benzothiazolyl, quinolyl, 3H-imidazo [4,5-b] pyridyl,

By C _1-6The optional pyrryl that replaces of alkyl,

By 1 or 2 C _1-6The optional pyrazolyl that replaces of alkyl,

By 1 or 2 C _1-6The optional replacement of alkyl De isoxazolyl,

By chlorine, nitro, cyano group or C _1-6The optional 2-thienyl that replaces of alkyl,

By chlorine, nitro, cyano group or C _1-6The optional 3-thienyl that replaces of alkyl,

By C _1-6The optional piperidyl that replaces of alkoxy carbonyl or benzyloxycarbonyl,

By the optional phenyl that replaces of 1-3 substituting group, substituting group is selected from: fluorine, chlorine, hydroxyl, nitro, cyano group, carboxyl, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Alkoxy carbonyl, amino, N-(C _1-6Alkyl) amino, N-(C _1-6Acyl group) amino, N-(C _1-6Alkoxy carbonyl) amino, N, N-two (C _1-6Alkyl) amino, N-(formyl radical)-N-C _1-6Alkylamino, C _1-6Alkylthio, C _1-6Alkyl sulphonyl, sulfamyl, pyrryl, imidazolyl, pyrazolyl and by C _1-6The optional piperazinyl that replaces of alkyl,

By the optional pyridyl that replaces of 1 or 2 substituting group, substituting group is selected from: chlorine, hydroxyl, carboxyl, C _1-6Alkoxyl group, C _1-6Alkylthio, amino, N-(C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(C _1-6Acyl group) amino, N-(C _1-6Alkyl) sulfuryl amino, N-[N, N-two (C _1-6Alkyl) aminomethylene] amino, C _1-6Alkoxyl phenyl C _1-6Alkoxyl group and by the optional C that replaces of three halogens _1-6Alkyl,

By C _1-6The optional piperazinyl that replaces of alkyl,

Be selected from C by 1 or 2 _1-6Alkyl, pyridyl and N-(C _1-6Alkoxy carbonyl) the optional 1,3-thiazoles base that replaces of An Ji substituting group,

By C _1-6The optional indyl that replaces of alkyl,

By C _1-6Alkyl or three halo C _1-6The optional benzimidazolyl-that replaces of alkyl,

By C _1-61,2 of the optional replacement of alkyl, 3-benzotriazole base,

By the optional C that replaces of three halogens _1-61 of the optional replacement of alkyl, the 8-naphthyridinyl,

By the optional C that replaces of three halogens, phenyl, phenoxy group or thienyl _1-6Alkyl,

Or

By the optional C that replaces of phenyl, phenoxy group or thienyl _1-6Alkoxyl group;

R ²Expression fluorine, chlorine, bromine, hydroxyl, nitro, vinyl, cyano group, amino, glycyl oxygen base, N-(C _1-6Alkyl) amino, N, N-two (C _1-6Alkyl) amino, N-(hydroxyl C _1-6Alkyl)-N-(C _1-6Alkyl) amino, 2-furyl, piperidino-(1-position only), morpholino, phenyl,

By the optional pyrrolidyl that replaces of kharophen,

By the optional piperidino-(1-position only) that replaces of hydroxyl,

By methyl, benzyl, C _1-6The optional piperazinyl that replaces of alkoxy carbonyl or aminocarboxyl,

By the optional C that replaces of cyano group, trifluoro, carboxyl, methoxycarbonyl, aminocarboxyl, tert-butoxycarbonyl, THP trtrahydropyranyl or morpholino _1-6Alkyl,

Or

By hydroxyl, cyano group, methoxyl group, methoxycarbonyl, tert-butoxycarbonyl, carboxyl, glycyl, dimethylamino, aminocarboxyl, methylamino carbonyl, dimethylamino carbonyl, sec.-propyl aminocarboxyl, fluoro-benzylamino formyl radical, cyclopropyl, pyrrolidyl, piperidino-(1-position only), THP trtrahydropyranyl, morpholino, morpholino carbonyl, tetrazyl, 2-oxo-1,3-oxazolidine-4-base, O-phthalic imide-N-base or hydroxyl C _1-6The optional C that replaces of alkene oxygen base _1-6Alkoxyl group,

R ³Expression H;

R ⁴Expression H;

R ⁵Expression H; With

R ⁶Expression H.

7. the formula of claim 1 (I) fused pyrrole pyrimidine derivatives, its change or stereoisomeric forms in any ratio or its salt:

Wherein

X represents CR ⁵R ⁶Or NH;

Y ¹Expression N;

Y ²And Y ³Expression CR ³R ⁴

Between chemical bond represent singly-bound,

Z ³And Z ⁴Expression CH;

Z ¹And Z ²Represent CH or CR respectively ²

R ¹Expression by hydroxyl, amino, kharophen, methoxyl group benzyloxy base or amino optional 3H-imidazo [4, the 5-b] pyridyl that replaces of sulfonyloxy methyl, benzimidazolyl-, pyridyl,

Or

By the optional 1,3-thiazoles base that replaces of 1 or 2 methyl;

R ²Expression fluorine, chlorine, bromine, morpholino, piperazinyl, methylpiperazine base, methyl, trifluoromethyl, or

By hydroxyl, cyano group, carboxyl, dimethylamino carbonyl, THP trtrahydropyranyl, morpholino, morpholino carbonyl, tetrazyl or O-phthalic imide-optional C that replaces of N-base _1-6Alkoxyl group;

R ³Expression H;

R ⁴Expression H;

R ⁵Expression _HWith

R ⁶Expression H.

8. the formula of claim 1 (I) fused pyrrole pyrimidine derivatives, its change or stereoisomeric forms in any ratio or its salt:

Wherein

X represents CR ⁵R ⁶Or NH;

Y ¹Expression N;

Y ²And Y ³Expression CR ³R ⁴

Between chemical bond represent singly-bound,

Z ¹, Z ³Represent CH with Z4;

Z ²Expression CR ²

R ¹Expression by hydroxyl, amino, kharophen, methoxyl group benzyloxy base or amino optional 3H-imidazo [4, the 5-b] pyridyl that replaces of sulfonyloxy methyl, benzimidazolyl-, pyridyl,

Or

By the optional 1,3-thiazoles base that replaces of 1 or 2 methyl;

R ²Expression fluorine, chlorine, bromine, morpholino, piperazinyl, methylpiperazine base, methyl, trifluoromethyl,

By hydroxyl, cyano group, carboxyl, dimethylamino carbonyl, THP trtrahydropyranyl, morpholino, morpholino carbonyl, tetrazyl or O-phthalic imide-optional C that replaces of N-base _1-6Alkoxyl group;

R ³Expression H;

R ⁴Expression H;

R ⁵Expression H; With

R ⁶Expression H.

9. the formula of claim 1 (I) fused pyrrole pyrimidine derivatives, its change or steric isomer or its salt, wherein said derivative is selected from following compound:

N-(7,8-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) niacinamide;

2-(7,8-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1-pyridin-3-yl vinyl alcohol;

N-(7,8-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1H-benzoglyoxaline-5-carboxylic acid amides;

6-(kharophen)-N-(7,8-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) niacinamide;

N-{5-[2-(7,8-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1-hydroxyl vinyl] pyridine-2-yl } ethanamide;

2-(5-[2-hydroxyl-2-pyridin-3-yl vinyl]-7-methoxyl group-2, the 3-glyoxalidine is [1,2-c] quinazoline-8-yl also } the oxygen base)-N,N-dimethylacetamide;

2-[7-methoxyl group-8-(tetrahydrochysene-2H-pyrans-2-ylmethoxy)-2, the 3-glyoxalidine is [1,2-c] quinazoline-5-yl also]-1-pyridin-3-yl vinyl alcohol;

2-[8-(2-hydroxyl-oxethyl)-7-methoxyl group-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also]-1-pyridin-3-yl vinyl alcohol;

(5-[2-hydroxyl-2-pyridin-3-yl vinyl]-7-methoxyl group-2, the 3-glyoxalidine is [1,2-c] quinazoline-8-yl also } the oxygen base) acetate;

4-(5-[2-hydroxyl-2-pyridin-3-yl vinyl]-7-methoxyl group-2, the 3-glyoxalidine is [1,2-c] quinazoline-8-yl also } the oxygen base) butyric acid;

(5-[2-hydroxyl-2-pyridin-3-yl vinyl]-7-methoxyl group-2, the 3-glyoxalidine is [1,2-c] quinazoline-8-yl also } the oxygen base) acetonitrile;

2-[7-methoxyl group-8-(2H-tetrazolium-5-ylmethoxy)-2, the 3-glyoxalidine is [1,2-c] quinazoline-5-yl also]-1-pyridin-3-yl vinyl alcohol;

2-[7-methoxyl group-8-(4-morpholine-4-base-4-oxo butoxy)-2, the 3-glyoxalidine is [1,2-c] quinazoline-5-yl also]-1-pyridin-3-yl vinyl alcohol;

5-[1-hydroxyl-2-(8-morpholine-4-base-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) vinyl] pyridine-3-alcohol;

N-(2, the 3-glyoxalidine is [1,2-c] quinazoline-5-yl also)-5-hydroxy nicotinoyl amine;

6-(kharophen)-N-(7,9-dimethoxy-8-methyl-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) niacinamide;

N-(8,9-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-5 hydroxy nicotinoyl amines;

5-hydroxy-n-(7-methoxyl group-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) niacinamide;

N-(7,8-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-5-[(4-methoxy-benzyl) oxygen base] niacinamide;

N-(7,8-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-5 hydroxy nicotinoyl amines;

5-hydroxy-n-[8-(trifluoromethyl)-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also] niacinamide;

N-{8-[3-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) propoxy-]-2, the 3-glyoxalidine is [1,2-c] quinazoline-5-yl also } niacinamide;

N-(7-bromo-8-methoxyl group-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) niacinamide;

6-amino-N-(8-methoxyl group-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) niacinamide;

1-(1H-benzoglyoxaline-5-yl)-2-(8,9-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) vinyl alcohol;

2-(8,9-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1-(2,4-dimethyl-1,3-thiazoles-5-yl) vinyl alcohol;

N-(9-methoxyl group-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1H-benzoglyoxaline-5-carboxylic acid amides;

N-(8-bromo-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) niacinamide;

N-(8-bromo-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1H-benzoglyoxaline-5-carboxylic acid amides;

N-(8-methoxyl group-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1H-benzoglyoxaline-5-carboxylic acid amides;

N-(8-methyl-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1H-benzoglyoxaline-5-carboxylic acid amides;

N-[8-(trifluoromethyl)-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also]-1H-benzoglyoxaline-5-carboxylic acid amides;

N-(7-fluoro-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1H-benzoglyoxaline-5 carboxylic acid amides;

N-(7-methoxyl group-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) niacinamide;

N-(8-chloro-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1H-benzoglyoxaline-5-carboxylic acid amides;

6-(kharophen)-N-(8-morpholine-4-base-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) niacinamide;

1-(1H-benzoglyoxaline-5-yl)-2-(8-morpholine-4-base-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) vinyl alcohol;

N-{5-[1-hydroxyl-2-(8-morpholine-4-base-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) vinyl] pyridine-2-yl } ethanamide;

6-methyl-N-(8-morpholine-4-base-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also) niacinamide;

1-(1H-benzoglyoxaline-5-yl)-2-[8-(4-methylpiperazine-1-yl)-2, the 3-glyoxalidine is [1,2-c] quinazoline-5-yl also] vinyl alcohol;

N-(2, the 3-glyoxalidine is [1,2-c] quinazoline-5-yl also)-3H-imidazo [4,5-b] pyridine-6-carboxylic acid amides;

N-(7,8-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-3H-imidazo [4,5-b] pyridine-6-carboxylic acid amides;

N-[7-(trifluoromethyl)-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also]-1H-benzoglyoxaline-5-carboxylic acid amides;

N-(7,9-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1H-benzoglyoxaline-5-carboxylic acid amides;

N-{5-[2-(7,9-dimethoxy-8-methyl-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1-hydroxyl vinyl] pyridine-2-yl } ethanamide;

N-{5-[2-(7-bromo-9-methyl-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1-hydroxyl vinyl] pyridine-2-yl } ethanamide; With

2-(8,9-dimethoxy-2,3-glyoxalidine be [1,2-c] quinazoline-5-yl also)-1-pyridin-3-yl vinyl alcohol.

10. medicine, it contains the fused pyrrole pyrimidine derivatives of claim 1, and its change or stereoisomer form or pharmaceutically useful salt are as activeconstituents.

11. the medicine of claim 10, it also contains one or more pharmaceutically useful vehicle.

12. the medicine of claim 10, fused pyrrole pyrimidine derivatives wherein, its change or stereoisomer form or pharmaceutically useful salt are the PI3K inhibitor.

13. the medicine of claim 10, fused pyrrole pyrimidine derivatives wherein, its change or stereoisomer form or pharmaceutically useful salt are the PI3K gamma inhibitors.

14. be used to prevent and/or treat the medicine of the claim 10 of inflammation or immunomodulatory disease.

15. be used to prevent and/or treat asthma, rhinitis, anaphylactic disease, from the medicine of the claim 14 of immunopathology, rheumatic arthritis, Graves disease and arteriosclerosis.

16. be used to prevent and/or treat the medicine of the claim 10 of neurodegenerative disease, presenile dementia or focus ischemic.

17. be used to prevent and/or treat the medicine of the claim 10 of diabetes, cancer, cardiac contractility disease, heart failure, local asphyxia, pulmonary hypertension, renal failure or cardiac hypertrophy.

18. the fused pyrrole pyrimidine derivatives of claim 1, its change or stereoisomer form or pharmaceutically useful salt production are used to prevent and/or treat the purposes of the medicine of inflammatory diseases or symptom.

19. the fused pyrrole pyrimidine derivatives of claim 1, its change or stereoisomer form or pharmaceutically useful salt production are used to prevent and/or treat asthma, rhinitis, anaphylactic disease or from the purposes of immunopathologic medicine.

20. the fused pyrrole pyrimidine derivatives of claim 1, its change or stereoisomer form or pharmaceutically useful salt production are used to prevent and/or treat the purposes of the medicine of diabetes, cancer, cardiac contractility disease, heart failure, local asphyxia, pulmonary hypertension, renal failure and cardiac hypertrophy.

21. the fused pyrrole pyrimidine derivatives of claim 1, its change or stereoisomer form or pharmaceutically useful salt production are used to prevent and/or treat the purposes with the medicine of active diseases associated of PI3K or symptom.

22. the fused pyrrole pyrimidine derivatives of claim 1, its change or stereoisomer form or pharmaceutically useful salt production are used for the treatment of and/or the purposes of the medicine of prevention and PI3K-gamma activity diseases associated or symptom.

23. the method for control inflammatory diseases or symptom in human body and animal, it comprises that administration PI3K suppresses the compound of the claim 1 of significant quantity.

24. the method for control inflammatory diseases in human body and animal, it comprises that administration PI3K-γ suppresses the compound of the claim 1 of significant quantity.

25. in human body and animal, control asthma, rhinitis, anaphylactic disease or from immunopathologic method, it comprises that administration PI3K-γ suppresses the compound of the claim 1 of significant quantity.

26. the method for control of diabetes, cancer, cardiac contractility disease, heart failure, local asphyxia, pulmonary hypertension, renal failure and cardiac hypertrophy in human body and animal, it comprises that administration PI3K-γ suppresses the compound of the claim 1 of significant quantity.